Methods of treatment using Anti-c-met antibody drug conjugates

Abstract

The present application pertains to, among other things, improved methods of treating solid tumors, including, but not limited to, non-small cell lung cancer ("NSCLC") tumors, gastroesophageal adenocarcinoma ("GEA") tumors, colorectal cancer ("CRC") tumors, and MET gene amplified advanced solid tumors, using an anti-c-Met antibody drug conjugate ("anti-c-Met ADC"). In specific embodiments, the anti-c-Met ADC consists of a c-Met- targeting antibody telisotuzumab conjugated to a potent topoisomerase 1 inhibitor (Topli) payload.

Description

METHODS OF TREATMENT USING ANTI-C-MET ANTIBODY DRUG CONJUGATES 1. CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application Nos. 63 / 503,929, filed May 23, 2023, and 63 / 555,506, filed February 20, 2024, both of which are incorporated by reference herein in their entireties. 2. SEQUENCE LISTING

[0002] The instant application contains a Sequence Listing which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. Said XML copy, created on May 4, 2023, is named 13371-287-888_SEQLISTING.xml and is 20,912 bytes in size. 3. TECHNICAL FIELD

[0003] The present application pertains to, among other things, improved methods of treating solid tumors, including non-small cell lung cancer (“NSCLC”) tumors, gastroesophageal adenocarcinoma (“GEA”) tumors, colorectal cancer (“CRC”) tumors, MET gene amplified advanced solid tumors, hepatocellular carcinoma (HCC) tumors, biliary tract cancer (BTC) tumors, pancreatic ductal adenocarcinoma (PDAC) tumors, esophageal squamous cell carcinoma (ESCC) tumors, triple-negative breast cancer (TNBC) tumors, hormone receptor- positive) / human epidermal growth factor receptor 2 negative breast cancer (HR+ / HER2- BC) tumors, head and neck squamous cell carcinoma (HNSCC) tumors, or MET gene mutated tumors by administering to a human subject having said solid tumor a therapeutically effective amount of an anti-c-Met ADC. using an anti-c-Met antibody drug conjugate (“anti- c-Met ADC”). In specific embodiments, the anti-c-Met ADC consists of a c-Met-targeting antibody telisotuzumab conjugated to a potent topoisomerase 1 inhibitor (Top1i) payload. 4. BACKGROUND

[0004] c-Met is a signaling tyrosine kinase receptor expressed on the surface of epithelial and endothelial cells. Activation of c-Met by hepatocyte growth factor (HGF), its only known ligand, has been shown to control cell proliferation, angiogenesis, survival, and cellular motility. 1 158929154.2

[0005] Antibody drug conjugates (ADCs) are a new class of therapeutics comprising an antibody conjugated to a cytotoxic drug via a chemical linker. The therapeutic concept of ADCs is to combine binding capabilities of an antibody with a cytotoxic drug, where the antibody is used to deliver the cytotoxic drug to a tumor cell by means of binding to a target surface antigen, including target surface antigens that are overexpressed or amplified in the tumor cells.

[0006] There remains a need in the art for developing therapeutic methods using ADCs to treat solid tumors, in particular to find therapeutically effective doses and dosing regimens of ADCs. 5. SUMMARY

[0007] The present application discloses methods of treating a non-squamous non-small cell lung cancer (“NSCLC”) tumor that expresses c-Met, comprising administering intravenously every three weeks to a human subject having said NSCLC tumor a therapeutically effective amount of 1.6 mg / kg, 2.4 mg / kg, 3.0 mg / kg, 3.5 mg / kg, 4.0 mg / kg, or 6.0 mg / kg of an anti-c- Met antibody drug conjugate (“anti-c-Met ADC”) having the following structure:

[0008] wherein n is 2, 4, 6, 8, or 10, and wherein Ab is telisotuzumab (such an anti-c-Met ADC is also referred to in this disclosure as ADC1), thereby treating said NSCLC tumor.

[0009] In some embodiments, the NSCLC tumor that expresses c-Met is refractory or relapsed.

[0010] In some embodiments, the NSCLC tumor that expresses c-Met expresses wild type epidermal growth factor receptor (EGFR-wt).

[0011] In some embodiments, the NSCLC tumor that expresses c-Met expresses mutated EGFR (EGFR-mu). 2 158929154.2

[0012] In some embodiments, the NSCLC tumor that expresses c-Met is an advanced solid tumor that has progressed on all standard of care therapy and is not amenable to surgical resection or other approved therapeutic options that have demonstrated clinical benefit.

[0013] In some embodiments, the NSCLC tumor that expresses c-Met has progressed after treatment with at least platinum-based chemotherapy and an immune checkpoint inhibitor and / or appropriate targeted therapy.

[0014] In some embodiments, the NSCLC tumor that expresses c-Met has progressed after treatment with at least platinum-based chemotherapy doublet and / or tyrosine kinase inhibitor(s).

[0015] In some embodiments, the human subject has had no more than 2 lines of prior cytotoxic chemotherapy excluding adjuvant therapy.

[0016] In some embodiments, administration of the anti-c-Met ADC provides an overall response rate that is greater than 15%, greater than 20%, greater than 25%, greater than 30%, greater than 35%, greater than 40%, greater than 45%, greater than 50%, greater than 55%, greater than 60%, greater than 65%, greater than 70%, greater than 75%, or greater than 80%.

[0017] In some embodiments, administration of the anti-c-Met ADC achieves a partial response (PR) in the human subject.

[0018] In some embodiments, administration of the anti-c-Met ADC achieves a complete response (CR) in the human subject.

[0019] In some embodiments, administration of the anti-c-Met ADC achieves stable disease (SD) in the human subject.

[0020] In some embodiments, n has a value of 2.

[0021] In some embodiments, n has a value of 4.

[0022] In some embodiments, n has a value of 6.

[0023] In some embodiments, n has a value of 8.

[0024] In some embodiments, n has a value of 10.

[0025] In some embodiments, the anti-c-Met ADC has an average drug-antibody ratio (DAR) of about 5.4 to about 6.6. 3 158929154.2

[0026] In some embodiments, the NSCLC tumor that expresses c-Met is a refractory or relapsed NSCLC tumor, a therapeutically effective amount of 2.4 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to the human subject, the anti-c-Met ADC has an average DAR of about 6, and administration of the anti-c-Met ADC achieves PR in the human subject.

[0027] In some embodiments, the NSCLC tumor that expresses c-Met is a refractory or relapsed NSCLC tumor, a therapeutically effective amount of 3.0 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to the human subject, the anti-c-Met ADC has an average DAR of about 6, and administration of the anti-c-Met ADC achieves PR in the human subject.

[0028] In some embodiments, the NSCLC tumor that expresses c-Met is a refractory or relapsed NSCLC tumor, a therapeutically effective amount of 2.4 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to a plurality of human subjects, the anti-c-Met ADC has an average DAR of about 6, and administration of the anti-c-Met ADC provides an overall response rate that is greater than 25%.

[0029] In some embodiments, the NSCLC tumor that expresses c-Met is a refractory or relapsed NSCLC tumor, a therapeutically effective amount of 3.0 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to a plurality of human subjects, the anti-c-Met ADC has an average DAR of about 6, and administration of the anti-c-Met ADC provides an overall response rate that is greater than 25%.

[0030] The present application further discloses a method of treating a gastroesophageal adenocarcinoma (“GEA”) tumor that expresses c-Met, comprising administering intravenously every three weeks to a human subject having said GEA tumor a therapeutically effective amount of 1.6 mg / kg, 2.4 mg / kg, 3.0 mg / kg, 3.5 mg / kg, 4.0 mg / kg, or 6.0 mg / kg of an anti-c-Met ADC having the following structure:4 158929154.2

[0031] wherein n is 2, 4, 6, 8, or 10, and wherein Ab is telisotuzumab, thereby treating said GEA tumor.

[0032] In some embodiments, the GEA tumor that expresses c-Met is refractory or relapsed.

[0033] In some embodiments, the GEA tumor that expresses c-Met is advanced histopathologically or cytologically confirmed GEA that has progressed after treatment with at least 1 prior cytotoxic chemotherapeutic regimen for locally advanced or metastatic disease and is not amenable to surgical resection, and the human subject has not received more than 2 prior lines of cytotoxic chemotherapy regimens.

[0034] In some embodiments, the GEA tumor that expresses c-Met has progressed on an immune checkpoint inhibitor.

[0035] In some embodiments, the GEA tumor that expresses c-Met has progressed on HER2- directed therapies.

[0036] In some embodiments, administration of the anti-c-Met ADC provides an overall response rate that is greater than 25%, greater than 30%, greater than 35%, greater than 40%, greater than 45%, greater than 50%, greater than 55%, greater than 60%, greater than 65%, greater than 70%, greater than 75%, or greater than 80%.

[0037] In some embodiments, administration of the anti-c-Met ADC achieves a partial response (PR) in the human subject.

[0038] In some embodiments, administration of the anti-c-Met ADC achieves a complete response (CR) in the human subject.

[0039] In some embodiments, administration of the anti-c-Met ADC achieves stable disease (SD) in the human subject.

[0040] In some embodiments, n has a value of 2.

[0041] In some embodiments, n has a value of 4.

[0042] In some embodiments, n has a value of 6.

[0043] In some embodiments, n has a value of 8.

[0044] In some embodiments, n has a value of 10.

[0045] In some embodiments, the anti-c-Met ADC has an average DAR of about 5.4 to about 6.6. 5 158929154.2

[0046] In some embodiments, the GEA tumor that expresses c-Met is a refractory or relapsed GEA tumor, a therapeutically effective amount of 2.4 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to the human subject, the anti-c-Met ADC has an average DAR of about 6, and administration of the anti-c-Met ADC achieves PR in the human subject.

[0047] In some embodiments, the GEA tumor that expresses c-Met is a refractory or relapsed GEA tumor, a therapeutically effective amount of 3.0 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to the human subject, the anti-c-Met ADC has an average DAR of about 6, and administration of the anti-c-Met ADC achieves PR in the human subject.

[0048] In some embodiments, the GEA tumor that expresses c-Met is a refractory or relapsed GEA tumor, a therapeutically effective amount of 2.4 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to a plurality of human subjects, the anti-c-Met ADC has an average DAR of about 6, and administration of the anti-c-Met ADC provides an overall response rate that is greater than 25%.

[0049] In some embodiments, the GEA tumor that expresses c-Met is a refractory or relapsed GEA tumor, a therapeutically effective amount of 3.0 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to a plurality of human subjects, the anti-c-Met ADC has an average DAR of about 6, and administration of the anti-c-Met ADC provides an overall response rate that is greater than 25%.

[0050] The present application further discloses a method of treating a colorectal cancer (“CRC”) tumor that expresses c-Met, comprising administering intravenously every three weeks to a human subject having said CRC tumor a therapeutically effective amount of 0.8 mg / kg, 1.0 mg / kg, 1.2 mg / kg, 1.6 mg / kg, 2.0 mg / kg 2.4 mg / kg, 3.0 mg / kg, 3.5 mg / kg, 4.0 mg / kg, or 6.0 mg / kg of an anti-c-Met ADC having the following structure:6 158929154.2

[0051] wherein n is 2, 4, 6, 8, or 10, and wherein Ab is telisotuzumab, thereby treating said CRC tumor.

[0052] In some embodiments, the CRC tumor that expresses c-Met is refractory or relapsed.

[0053] In some embodiments, the CRC tumor that expresses c-Met is advanced histopathologically or cytologically confirmed CRC that does not harbor the BRAF V600E mutation and is not dMMR+ / MSI-Hi.

[0054] In embodiments, the CRC tumor that expresses c-Met is advanced histopathologically or cytologically confirmed CRC that harbors MET genomic alterations. In embodiments, the CRC tumor that expresses c-Met is advanced histopathologically or cytologically confirmed CRC that harbors KRAS genomic alterations. In embodiments, the CRC tumor that expresses c-Met is advanced histopathologically or cytologically confirmed CRC that harbors EGFR genomic alterations. In embodiments, only subjects with tumors that harbor one or more of the MET, KRAS or EGFR genomic alterations are treated and subjects with tumors that do not harbor said one or more mutations are excluded from treatment.

[0055] In embodiments, the CRC tumor that expresses c-Met is advanced histopathologically or cytologically confirmed CRC that does not harbor MET genomic alterations. In embodiments, the CRC tumor that expresses c-Met is advanced histopathologically or cytologically confirmed CRC that does not harbor KRAS genomic alterations. In embodiments, the CRC tumor that expresses c-Met is advanced histopathologically or cytologically confirmed CRC that does not harbor EGFR genomic alterations. In embodiments, only subjects with tumors that do not harbor one or more of the MET, KRAS or EGFR genomic alterations are treated, and subjects with tumors that do harbor said one or more mutations are excluded from treatment.

[0056] In some embodiments, the CRC tumor that expresses c-Met has progressed on any one or a combination of prior treatments including a fluoropyrimidine, oxaliplatin, irinotecan, an anti-EGFR antibody, and / or an anti-vascular endothelial growth factor monoclonal antibody.

[0057] In some embodiments, the CRC tumor that expresses c-Met has progressed on an applicable targeted therapy.

[0058] In some embodiments, administration of the anti-c-Met ADC provides an overall response rate that is greater than 10%, greater than 15%, greater than 20%, greater than 25%, greater than 30%, greater than 35%, greater than 40%, greater than 45%, greater than 50%, 7 158929154.2greater than 55%, greater than 60%, greater than 65%, greater than 70%, greater than 75%, or greater than 80%.

[0059] In some embodiments, administration of the anti-c-Met ADC achieves a partial response (PR) in the human subject.

[0060] In some embodiments, administration of the anti-c-Met ADC achieves a complete response (CR) in the human subject.

[0061] In some embodiments, administration of the anti-c-Met ADC achieves stable disease (SD) in the human subject.

[0062] In some embodiments, n has a value of 2.

[0063] In some embodiments, n has a value of 4.

[0064] In some embodiments, n has a value of 6.

[0065] In some embodiments, n has a value of 8.

[0066] In some embodiments, n has a value of 10.

[0067] In some embodiments, the anti-c-Met ADC has an average DAR of about 5.4 to about 6.6.

[0068] In some embodiments, the CRC tumor that expresses c-Met is a refractory or relapsed CRC tumor, a therapeutically effective amount of 2.4 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to the human subject, the anti-c-Met ADC has an average DAR of about 6, and administration of the anti-c-Met ADC achieves PR in the human subject.

[0069] In some embodiments, the CRC tumor that expresses c-Met is a refractory or relapsed CRC tumor, a therapeutically effective amount of 3.0 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to the human subject, the anti-c-Met ADC has an average DAR of about 6, and administration of the anti-c-Met ADC achieves PR in the human subject.

[0070] In some embodiments, the CRC tumor that expresses c-Met is a refractory or relapsed CRC tumor, a therapeutically effective amount of 2.4 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to a plurality of human subjects, the anti-c-Met ADC has an average DAR of about 6, and administration of the anti-c-Met ADC provides an overall response rate that is greater than 25%. 8 158929154.2

[0071] In some embodiments, the CRC tumor that expresses c-Met is a refractory or relapsed CRC tumor, a therapeutically effective amount of 3.0 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to a plurality of human subjects, the anti-c- Met ADC has an average DAR of about 6, and administration of the anti-c-Met ADC provides an overall response rate that is greater than 25%.

[0072] The present application further discloses a method of treating a MET gene amplified advanced solid tumor that expresses c-Met, comprising administering intravenously every three weeks to a human subject having said MET gene amplified advanced tumor a therapeutically effective amount of 1.6 mg / kg, 2.4 mg / kg, 3.0 mg / kg, 3.5 mg / kg, 4.0 mg / kg, or 6.0 mg / kg of an anti-c-Met ADC having the following structure:

[0073] wherein n is 2, 4, 6, 8, or 10, and wherein Ab is telisotuzumab, thereby treating said MET gene amplified advanced solid tumor.

[0074] In some embodiments, the MET gene amplified advanced solid tumor that expresses c-Met is refractory or relapsed.

[0075] In some embodiments, n has a value of 2.

[0076] In some embodiments, n has a value of 4.

[0077] In some embodiments, n has a value of 6.

[0078] In some embodiments, n has a value of 8.

[0079] In some embodiments, n has a value of 10.

[0080] In some embodiments, the anti-c-Met ADC has an average DAR of about 5.4 to about 6.6.

[0081] In some embodiments, the MET gene amplified advanced solid tumor that expresses c-Met is a refractory or relapsed MET gene amplified advanced solid tumor, a therapeutically 9 158929154.2effective amount of 2.4 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to the human subject, the anti-c-Met ADC has an average DAR of about 6, and administration of the anti-c-Met ADC achieves PR in the human subject.

[0082] In some embodiments, the MET gene amplified advanced solid tumor that expresses c-Met is a refractory or relapsed MET gene amplified advanced solid tumor, a therapeutically effective amount of 3.0 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to the human subject, the anti-c-Met ADC has an average DAR of about 6, and administration of the anti-c-Met ADC achieves PR in the human subject.

[0083] In some embodiments, the MET gene amplified advanced solid tumor that expresses c-Met is a refractory or relapsed MET gene amplified advanced solid tumor, a therapeutically effective amount of 2.4 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to a plurality of human subjects, the anti-c-Met ADC has an average DAR of about 6, and administration of the anti-c-Met ADC provides an overall response rate that is greater than 25%.

[0084] In some embodiments, the MET gene amplified advanced solid tumor that expresses c-Met is a refractory or relapsed MET gene amplified advanced solid tumor, a therapeutically effective amount of 3.0 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to a plurality of human subjects, the anti-c-Met ADC has an average DAR of about 6, and administration of the anti-c-Met ADC provides an overall response rate that is greater than 25%. 5.1 Illustrative Embodiments

[0085] The present disclosure includes the following non-limiting illustrative embodiments. 5.1.1 NSCLC Embodiments 1. A method of treating a non-squamous non-small cell lung cancer (“NSCLC”) tumor, comprising administering intravenously every three weeks to a human subject or population of human subjects having said NSCLC tumor a therapeutically effective amount of 1.6 mg / kg, 2.4 mg / kg, 3.0 mg / kg, 3.5 mg / kg, 4.0 mg / kg, or 6.0 mg / kg of an anti-c-Met antibody drug conjugate (“anti-c-Met ADC”) having the following structure: 10 158929154.2wherein n is 2, 4, 6, 8, or 10, and wherein Ab is telisotuzumab, thereby treating said NSCLC tumor. 2. The method of embodiment 1, wherein the NSCLC is refractory or relapsed. 3. The method of any one of embodiments 1-2, wherein the NSCLC tumor expresses wild type epidermal growth factor receptor (EGFR-wt). 4. The method of any one of embodiments 1-2, wherein the NSCLC tumor expresses mutated EGFR (EGFR-mu). 5. The method of any one of embodiments 1-2, wherein the NSCLC tumor is an advanced solid tumor that has progressed on all standard of care therapy and is not amenable to surgical resection or other approved therapeutic options that have demonstrated clinical benefit. 6. The method of embodiment 5, wherein the NSCLC tumor has progressed after treatment with at least platinum-based chemotherapy and an immune checkpoint inhibitor and / or appropriate targeted therapy. 7. The method of embodiment 5, wherein the NSCLC tumor has progressed after treatment with at least platinum-based chemotherapy doublet and / or tyrosine kinase inhibitor(s). 8. The method of any one of embodiments 5-7, wherein the human subject has had no more than 2 lines of prior cytotoxic chemotherapy excluding adjuvant therapy. 9. The method of any one of embodiments 1-8, wherein administration of the anti-c-Met ADC provides an overall response rate that is greater than 25%, greater than 30%, greater than 35%, greater than 40%, greater than 45%, greater than 50%, greater than 55%, greater than 60%, greater than 65%, greater than 70%, greater than 75%, or greater than 80%. 10. The method of any one of embodiments 1-9, wherein administration of the anti-c-Met ADC achieves a partial response (PR) in the human subject. 11 158929154.211. The method of any one of embodiments 1-9, wherein administration of the anti-c-Met ADC achieves a complete response (CR) in the human subject. 12. The method of any one of embodiments 1-9, wherein administration of the anti-c-Met ADC achieves stable disease (SD) in the human subject. 13. The method of any one of embodiments 1-12, wherein n has a value of 2. 14. The method of any one of embodiments 1-12, wherein n has a value of 4. 15. The method of any one of embodiments 1-12, wherein n has a value of 6. 16. The method of any one of embodiments 1-12, wherein n has a value of 8. 17. The method of any one of embodiments 1-12, wherein n has a value of 10. 18. The method of any one of embodiments 1-17, wherein the anti-c-Met ADC is in a pharmaceutical formulation having an average drug-antibody ratio (DAR) of about 5.4 to about 6.6. 19. The method of any one of embodiments 1-17, wherein the NSCLC tumor is a refractory or relapsed NSCLC tumor, wherein a therapeutically effective amount of 2.4 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to the human subject, wherein the anti-c-Met ADC has an average DAR of about 6, and wherein administration of the anti-c-Met ADC achieves PR in the human subject. 20. The method of any one of embodiments 1-17, wherein the NSCLC tumor is a refractory or relapsed NSCLC tumor, wherein a therapeutically effective amount of 3.0 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to the human subject, wherein the anti-c-Met ADC has an average DAR of about 6, and wherein administration of the anti-c-Met ADC achieves PR in the human subject. 21. The method of any one of embodiments 1-17 and 19, wherein the NSCLC tumor is a refractory or relapsed NSCLC tumor, wherein a therapeutically effective amount of 2.4 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to a plurality of human subjects, wherein the anti-c-Met ADC has an average DAR of about 6, and wherein administration of the anti-c-Met ADC provides an overall response rate that is greater than 25%. 22. The method of any one of embodiments 1-17 and 20, wherein the NSCLC tumor is a refractory or relapsed NSCLC tumor, wherein a therapeutically effective amount of 3.0 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to a plurality of human subjects, wherein the anti-c-Met ADC has an average DAR of 12 158929154.2about 6, and wherein administration of the anti-c-Met ADC provides an overall response rate that is greater than 25%. 23. The method of embodiment 1, wherein the tumor harbors a MET gene mutation. 24. The method of any one of embodiments 1-23, wherein the tumor expresses c-Met. 25. The method of any one of claims 1-24, wherein the tumor harbors a MET gene mutation. 5.1.2 GEA Embodiments 1. A method of treating a gastroesophageal adenocarcinoma (“GEA”) tumor, comprising administering intravenously every three weeks to a human subject or population of human subjects having said GEA tumor a therapeutically effective amount of 1.6 mg / kg, 2.4 mg / kg, 3.0 mg / kg, 3.5 mg / kg, 4.0 mg / kg, or 6.0 mg / kg of an anti-c-Met ADC having the following structure:wherein n is 2, 4, 6, 8, or 10, and wherein Ab is telisotuzumab, thereby treating said GEA tumor. 2. The method of embodiment 1, wherein the GEA tumor is refractory or relapsed. 3. The method of embodiment 2, wherein the GEA tumor has progressed on an immune checkpoint inhibitor. 4. The method of any one of embodiments 1-3, wherein the GEA tumor has progressed on HER2-directed therapies. 5. The method of any one of embodiments 1-4, wherein administration of the anti-c-Met ADC provides an overall response rate that is greater than 25%, greater than 30%, greater than 35%, greater than 40%, greater than 45%, greater than 50%, greater than 55%, greater than 60%, greater than 65%, greater than 70%, greater than 75%, or greater than 80%. 13 158929154.26. The method of any one of embodiments 1-5, wherein administration of the anti-c-Met ADC achieves a partial response (PR) in the human subject. 7. The method of any one of embodiments 1-5, wherein administration of the anti-c-Met ADC achieves a complete response (CR) in the human subject. 8. The method of any one of embodiments 1-5, wherein administration of the anti-c-Met ADC achieves stable disease (SD) in the subject. 9. The method of any one of embodiments 1-8, wherein n has a value of 2. 10. The method of any one of embodiments 1-8, wherein n has a value of 4. 11. The method of any one of embodiments 1-8, wherein n has a value of 6. 12. The method of any one of embodiments 1-8, wherein n has a value of 8. 13. The method of any one of embodiments 1-8, wherein n has a value of 10. 14. The method of any one of embodiments 1-13, wherein the anti-c-Met ADC is in a pharmaceutical formulation having an average drug-antibody ratio (DAR) of about 5.4 to about 6.6. 15. The method of any one of embodiments 1-13, wherein the GEA tumor is a refractory or relapsed GEA tumor, wherein a therapeutically effective amount of 2.4 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to the human subject, wherein the anti-c-Met ADC is in a pharmaceutical formulation having an average drug-antibody ratio (DAR) of about 6, and wherein administration of the anti- c-Met ADC achieves PR in the human patient. 16. The method of any one of embodiments 1-13, wherein the GEA tumor is a refractory or relapsed GEA tumor, wherein a therapeutically effective amount of 3.0 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to the human subject, wherein the anti-c-Met ADC is in a pharmaceutical formulation having an average drug-antibody ratio (DAR) of about 6, and wherein administration of the anti- c-Met ADC achieves PR in the human patient. 17. The method of any one of embodiments 1-13 and 15, wherein the GEA tumor is a refractory or relapsed GEA tumor, wherein a therapeutically effective amount of 2.4 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to a plurality of human subjects, wherein the anti-c-Met ADC is in a pharmaceutical formulation having an average drug-antibody ratio (DAR) of about 6, and wherein 14 158929154.2administration of the anti-c-Met ADC provides an overall response rate that is greater than 25%. 18. The method of any one of embodiments 1-13 and 16, wherein the GEA tumor is a refractory or relapsed GEA tumor, wherein a therapeutically effective amount of 3.0 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to a plurality of human subjects, wherein the anti-c-Met ADC is in a pharmaceutical formulation having an average drug-antibody ratio (DAR) of about 6, and wherein administration of the anti-c-Met ADC provides an overall response rate that is greater than 25%. 19. The method of embodiment 1, wherein the anti-c-Met ADC is administered in combination with an anti-PD1 or anti-PD-L1 antibody. 20. The method of embodiment 19, wherein the anti-c-Met ADC is administered in combination with an anti-PD1 antibody, wherein the anti-PD1 antibody is budigalimab, nivolumab, pembrolizumab, cemiplimab, dostarlimab, retifanlimab or toripalimab. 21. The method of embodiment 19, wherein the anti-c-Met ADC is administered in combination with an anti-PD-L1 antibody, wherein the anti-PD-L1 antibody is atezolizumab, avelumab, durvalumab. 22. The method of embodiment 19, 20 or 21, wherein the anti-c-Met ADC is administered in combination with fluorouracil (5-FU) and leucovorin (LV) / folinic acid. 23. The method of embodiment 22, wherein the anti-c-Met ADC is administered at a dose of 2.4 or 3.0 mg / kg once every four weeks, 5-FU is administered at a dose of 2400 mg / m2once every two weeks and leucovorin is administered at a dose of 400 mg / m2once every two weeks. 24. The method of embodiment 22, wherein the anti-c-Met ADC is administered at a dose of 2.4 or 3.0 mg / kg once every three weeks, 5-FU is administered at a dose of 2400 mg / m2once every two weeks and leucovorin is administered at a dose of 400 mg / m2once every two weeks. 25. The method of embodiment 22, wherein the anti-c-Met ADC is administered at a dose of 1.2 or 1.6 mg / kg once every two weeks, 5-FU is administered at a dose of 2400 mg / m2once every two weeks and leucovorin administered at a dose of 400 mg / m2once every two weeks. 15 158929154.226. The method of embodiment 1, wherein the anti-c-Met ADC is administered in combination with fluorouracil (5-FU), leucovorin (LV) / folinic acid, and budigalimab, and wherein the anti-c-Met ADC is administered at a dose of 2.4 or 3.0 mg / kg once every four weeks, budigalimab is administered at a dose of 500 mg once every four weeks, 5-FU is administered at a dose of 2400 mg / m2once every two weeks and leucovorin is administered at a dose of 400 mg / m2once every two weeks. 27. The method of embodiment 1, wherein the anti-c-Met ADC is administered in combination with fluorouracil (5-FU), leucovorin (LV) / folinic acid, and budigalimab, and wherein the anti-c-Met ADC is administered at a dose of 1.2 or 1.6 mg / kg once every two weeks, budigalimab is administered at a dose of 250 mg once every two weeks, 5-FU is administered at a dose of 2400 mg / m2once every two weeks and leucovorin administered at a dose of 400 mg / m2once every two weeks 28. The method of any one of embodiments 1-27, wherein the tumor expresses c-Met. 29. The method of any one of embodiments 1-28, wherein the tumor harbors a MET gene mutation. 5.1.3 CRC Embodiments 1. A method of treating a colorectal cancer (“CRC”) tumor, comprising administering intravenously every three weeks to a human subject or population of human subjects having said CRC tumor a therapeutically effective amount of 0.8 mg / kg, 1.0 mg / kg, 1.2 mg / kg, 1.6 mg / kg, 2.0 mg / kg, 2.4 mg / kg, 3.0 mg / kg, 3.5 mg / kg, 4.0 mg / kg, or 6.0 mg / kg of an anti-c-Met ADC having the following structure:wherein n is 2, 4, 6, 8, or 10, and wherein Ab is telisotuzumab, thereby treating said CRC tumor. 2. The method of embodiment 1, wherein the CRC tumor is refractory or relapsed. 16 158929154.23. The method of any one of embodiments 1-2, wherein the CRC tumor is advanced histopathologically or cytologically confirmed CRC that does not harbor the BRAF V600E mutation and is not dMMR+ / MSI-Hi. 4. The method of embodiment 3, wherein the CRC tumor has progressed on any one or a combination of prior treatments including a fluoropyrimidine, oxaliplatin, irinotecan, an anti-EGFR antibody, and / or an anti-vascular endothelial growth factor monoclonal antibody. 5. The method of embodiment 3 or 4, wherein the CRC tumor has progressed on an applicable targeted therapy. 6. The method of any one of embodiments 1-5, wherein administration of the anti-c-Met ADC provides an overall response rate that is greater than 25%, greater than 30%, greater than 35%, greater than 40%, greater than 45%, greater than 50%, greater than 55%, greater than 60%, greater than 65%, greater than 70%, greater than 75%, or greater than 80%. 7. The method of any one of embodiments 1-5, wherein administration of the anti-c-Met ADC achieves a partial response (PR) in the human subject. 8. The method of any one of embodiments 1-5, wherein administration of the anti-c-Met ADC achieves a complete response (CR) in the human subject. 9. The method of any one of embodiments 1-5, wherein administration of the anti-c-Met ADC achieves stable disease (SD) in the human subject. 10. The method of any one of embodiments 1-9, wherein n has a value of 2. 11. The method of any one of embodiments 1-9, wherein n has a value of 4. 12. The method of any one of embodiments 1-9, wherein n has a value of 6. 13. The method of any one of embodiments 1-9, wherein n has a value of 8. 14. The method of any one of embodiments 1-9, wherein n has a value of 10. 15. The method of any one of embodiments 1-9, wherein the anti-c-Met ADC is in a pharmaceutical formulation having an average drug-antibody ratio (DAR) of about 5.4 to about 6.6. 16. The method of any one of embodiments 1-14, wherein the CRC tumor is a refractory or relapsed CRC tumor, wherein a therapeutically effective amount of 2.4 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to the human 17 158929154.2subject, wherein the anti-c-Met ADC has an average DAR of about 6, and wherein administration of the anti-c-Met ADC achieves PR in the human subject. 17. The method of any one of embodiments 1-14, wherein the CRC tumor is a refractory or relapsed CRC tumor, wherein a therapeutically effective amount of 3.0 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to the human subject, wherein the anti-c-Met ADC is in a pharmaceutical formulation having an average drug-antibody ratio (DAR) of about 6, and wherein administration of the anti- c-Met ADC achieves PR in the human subject. 18. The method of any one of embodiments 1-14 and 16, wherein the CRC tumor is a refractory or relapsed CRC tumor, wherein a therapeutically effective amount of 2.4 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to a plurality of human subjects, wherein the anti-c-Met ADC is in a pharmaceutical formulation having an average drug-antibody ratio (DAR) of about 6, and wherein administration of the anti-c-Met ADC provides an overall response rate that is greater than 25%. 19. The method of any one of embodiments 1-14 and 17, wherein the CRC tumor is a refractory or relapsed CRC tumor, wherein a therapeutically effective amount of 3.0 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to a plurality of human subjects, wherein the anti-c-Met ADC is in a pharmaceutical formulation having an average drug-antibody ratio (DAR) of about 6, and wherein administration of the anti-c-Met ADC provides an overall response rate that is greater than 25%. 20. The method of embodiment 1, further comprising administration of bevacizumab at a dose of 7.5 mg / kg once every three weeks. 21. The method of embodiment 1, wherein the anti-C-Met ADC is administered once every two weeks or once every four weeks, further comprising administration of fluorouracil at a dose of 2400 g / m2once every two weeks, folinic acid at dose of 200 mg / m2once every two weeks, and bevacizumab at a dose of 5 mg / kg once every two weeks. 22. The method of embodiment 1, wherein the tumor harbors a MET gene mutation. 23. The method of any one of embodiments 1-22, wherein the tumor expresses c-Met. 24. The method of any one of claims 1-23, wherein the tumor harbors a MET gene mutation. 18 158929154.25.1.4 MET Amp Embodiments 1. A method of treating a MET gene amplified advanced solid tumor, comprising administering intravenously every three weeks to a human subject or population of human subjects having said MET gene amplified advanced tumor a therapeutically effective amount of 1.6 mg / kg, 2.4 mg / kg, 3.0 mg / kg, 3.5 mg / kg, 4.0 mg / kg, or 6.0 mg / kg of an anti-c-Met ADC having the following structure:wherein n is 2, 4, 6, 8, or 10, and wherein Ab is telisotuzumab, thereby treating said MET gene amplified advanced solid tumor. 2. The method of embodiment 1, wherein the MET gene amplified advanced solid tumor is refractory or relapsed. 3. The method of embodiment 1 or 2, wherein n has a value of 2. 4. The method of embodiment 1 or 2, wherein n has a value of 6. 5. The method of embodiment 1 or 2, wherein n has a value of 8. 6. The method of embodiment 1 or 2, wherein n has a value of 10. 7. The method of any one of embodiments 1-6, wherein the anti-c-Met ADC is in a pharmaceutical formulation having an average drug-antibody ratio (DAR) of about 5.4 to about 6.6. 8. The method of any one of embodiments 1-6, wherein the MET gene amplified advanced solid tumor is a refractory or relapsed MET gene amplified advanced solid tumor, wherein a therapeutically effective amount of 2.4 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to the human subject, wherein the anti-c-Met ADC is in a pharmaceutical formulation having an average drug- antibody ratio (DAR) of about, and wherein administration of the anti-c-Met ADC achieves PR in the human subject. 19 158929154.29. The method of any one of embodiments 1-6, wherein the MET gene amplified advanced solid tumor is a refractory or relapsed MET gene amplified advanced solid tumor, wherein a therapeutically effective amount of 3.0 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to the human subject, wherein the anti-c-Met ADC is in a pharmaceutical formulation having an average drug- antibody ratio (DAR) of about 6, and wherein administration of the anti-c-Met ADC achieves PR in the human subject. 10. The method of any one of embodiments 1-6 and 8, wherein the MET gene amplified advanced solid tumor is a refractory or relapsed MET gene amplified advanced solid tumor, wherein a therapeutically effective amount of 2.4 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to a plurality of human subjects, wherein the anti-c-Met ADC is in a pharmaceutical formulation having an average drug-antibody ratio (DAR) of about 6, and wherein administration of the anti- c-Met ADC provides an overall response rate that is greater than 25%. 11. The method of any one of embodiments 1-6 and 9, wherein the MET gene amplified advanced solid tumor is a refractory or relapsed MET gene amplified advanced solid tumor, wherein a therapeutically effective amount of 3.0 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to a plurality of human subjects, wherein the anti-c-Met ADC is in a pharmaceutical formulation having an average drug-antibody ratio (DAR) of about 6, and wherein administration of the anti- c-Met ADC provides an overall response rate that is greater than 25%. 12. The method of embodiment 1, wherein the tumor harbors a MET gene mutation. 13. The method of any one of embodiments 1-12, wherein the tumor expresses c-Met. 14. The method of any one of claims 1-13, wherein the tumor harbors a MET gene mutation. 5.1.5 HCC Embodiments 1. A method of treating a hepatocellular carcinoma (“HCC”) tumor, comprising administering intravenously every three weeks to a human subject or population of human subjects having said HCC tumor a therapeutically effective amount of 1.6 mg / kg, 2.0 mg / kg, 2.4 mg / kg, 3.0 mg / kg, 3.5 mg / kg, 4.0 mg / kg, or 6.0 mg / kg of an anti-c-Met ADC having the following structure: 20 158929154.2wherein n is 2, 4, 6, 8, or 10, and wherein Ab is telisotuzumab, thereby treating said HCC tumor. 2. The method of embodiment 1, wherein the HCC tumor is refractory or relapsed. 3. The method of any one of embodiments 1-2, wherein the HCC tumor is locally advanced or metastatic with disease progression during or after 1 prior line of systemic therapy. 4. The method of any one of embodiments 1-3, wherein administration of the anti-c-Met ADC provides an overall response rate that is greater than 10%, greater than 15%, greater than 20%, greater than 25%, greater than 30%, greater than 35%, greater than 40%, greater than 45%, greater than 50%, greater than 55%, greater than 60%, greater than 65%, greater than 70%, greater than 75%, or greater than 80%. 5. The method of any one of embodiments 1-4, wherein administration of the anti-c-Met ADC achieves a partial response (PR) in the human subject. 6. The method of any one of embodiments 1-4, wherein administration of the anti-c-Met ADC achieves a complete response (CR) in the human subject. 7. The method of any one of embodiments 1-4, wherein administration of the anti-c-Met ADC achieves stable disease (SD) in the subject. 8. The method of any one of embodiments 1-7, wherein n has a value of 2. 9. The method of any one of embodiments 1-7, wherein n has a value of 4. 10. The method of any one of embodiments 1-7, wherein n has a value of 6. 11. The method of any one of embodiments 1-7, wherein n has a value of 8. 12. The method of any one of embodiments 1-7, wherein n has a value of 10. 13. The method of any one of embodiments 1-12, wherein the anti-c-Met ADC is in a pharmaceutical formulation having an average DAR of about 5.4 to about 6.6. 21 158929154.214. The method of any one of embodiments 1-12, wherein the HCC tumor is a refractory or relapsed HCC tumor, wherein a therapeutically effective amount of 2.4 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to the human subject, wherein the anti-c-Met ADC is in a pharmaceutical formulation having an average drug-antibody ratio (DAR) of about 5.4 to about 6.6, and wherein administration of the anti-c-Met ADC achieves PR in the human patient. 15. The method of any one of embodiments 1-12, wherein the HCC tumor is a refractory or relapsed HCC tumor, wherein a therapeutically effective amount of 3.0 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to the human subject, wherein the anti-c-Met ADC is in a pharmaceutical formulation having an average drug-antibody ratio (DAR) of about 6, and wherein administration of the anti- c-Met ADC achieves PR in the human patient. 16. The method of any one of embodiments 1-12 and 14, wherein the HCC tumor is a refractory or relapsed HCC tumor, wherein a therapeutically effective amount of 2.4 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to a plurality of human subjects, wherein the anti-c-Met ADC is in a pharmaceutical formulation having an average drug-antibody ratio (DAR) of about 6, and wherein administration of the anti-c-Met ADC provides an overall response rate that is greater than 25%. 17. The method of any one of embodiments 1-12 and 15, wherein the HCC tumor is a refractory or relapsed HCC tumor, wherein a therapeutically effective amount of 3.0 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to a plurality of human subjects, wherein the anti-c-Met ADC is in a pharmaceutical formulation having an average drug-antibody ratio (DAR) of about 6, and wherein administration of the anti-c-Met ADC provides an overall response rate that is greater than 25%. 18. The method of embodiment 1, wherein the tumor harbors a MET gene mutation. 19. The method of any one of embodiments 1-18, wherein the tumor expresses c-Met. 20. The method of any one of claims 1-19, wherein the tumor harbors a MET gene mutation. 22 158929154.25.1.6 PDAC Embodiments 1. A method of treating a pancreatic ductal adenocarcinoma (“PDAC”) tumor, comprising administering intravenously every three weeks to a human subject or population of human subjects having said PDAC tumor a therapeutically effective amount of 1.6 mg / kg, 2.0 mg / kg, 2.4 mg / kg, 3.0 mg / kg, 3.5 mg / kg, 4.0 mg / kg, or 6.0 mg / kg of an anti-c-Met ADC having the following structure:wherein n is 2, 4, 6, 8, or 10, and wherein Ab is telisotuzumab, thereby treating said PDAC tumor. 2. The method of embodiment 1, wherein the PDAC tumor is refractory or relapsed. 3. The method of any one of embodiments 1-2, wherein the PDAC tumor is a histologically or cytologically confirmed advanced or metastatic PDAC tumor with disease progression during or after 1 systemic therapy. 4. The method of any one of embodiments 1-3, wherein administration of the anti-c-Met ADC provides an overall response rate that is greater than greater than 10%, greater than 15%, greater than 20%, 25%, greater than 30%, greater than 35%, greater than 40%, greater than 45%, greater than 50%, greater than 55%, greater than 60%, greater than 65%, greater than 70%, greater than 75%, or greater than 80%. 5. The method of any one of embodiments 1-4, wherein administration of the anti-c-Met ADC achieves a partial response (PR) in the human subject. 6. The method of any one of embodiments 1-4, wherein administration of the anti-c-Met ADC achieves a complete response (CR) in the human subject. 7. The method of any one of embodiments 1-4, wherein administration of the anti-c-Met ADC achieves stable disease (SD) in the subject. 8. The method of any one of embodiments 1-7, wherein n has a value of 2. 9. The method of any one of embodiments 1-7, wherein n has a value of 4. 23 158929154.210. The method of any one of embodiments 1-7, wherein n has a value of 6. 11. The method of any one of embodiments 1-7, wherein n has a value of 8. 12. The method of any one of embodiments 1-7, wherein n has a value of 10. 13. The method of any one of embodiments 1-12, wherein the anti-c-Met ADC is in a pharmaceutical formulation having an average DAR of about 5.4 to about 6.6. 14. The method of any one of embodiments 1-12, wherein the PDAC tumor is a histologically or cytologically confirmed advanced or metastatic PDAC tumor with disease progression during or after 1 systemic therapy, wherein a therapeutically effective amount of 2.4 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to the human subject, wherein the anti-c-Met ADC is in a pharmaceutical formulation having an average drug-antibody ratio (DAR) of about 5.4 to about 6.6, and wherein administration of the anti-c-Met ADC achieves PR in the human patient. 15. The method of any one of embodiments 1-12, wherein the PDAC tumor is a histologically or cytologically confirmed advanced or metastatic PDAC tumor with disease progression during or after 1 systemic therapy, wherein a therapeutically effective amount of 3.0 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to the human subject, wherein the anti-c-Met ADC is in a pharmaceutical formulation having an average drug-antibody ratio (DAR) of about 6, and wherein administration of the anti-c-Met ADC achieves PR in the human patient. 16. The method of any one of embodiments 1-12 and 14, wherein the PDAC tumor is a histologically or cytologically confirmed advanced or metastatic PDAC tumor with disease progression during or after 1 systemic therapy, wherein a therapeutically effective amount of 2.4 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to a plurality of human subjects, wherein the anti-c-Met ADC is in a pharmaceutical formulation having an average drug-antibody ratio (DAR) of about 6, and wherein administration of the anti-c-Met ADC provides an overall response rate that is greater than 25%. 17. The method of any one of embodiments 1-12 and 15, wherein the PDAC tumor is a histologically or cytologically confirmed advanced or metastatic PDAC tumor with disease progression during or after 1 systemic therapy, wherein a therapeutically effective amount of 3.0 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to a plurality of human subjects, wherein the anti-c-Met ADC is in 24 158929154.2a pharmaceutical formulation having an average drug-antibody ratio (DAR) of about 6, and wherein administration of the anti-c-Met ADC provides an overall response rate that is greater than 25%. 18. The method of embodiment 1, wherein the tumor harbors a MET gene mutation. 19. The method of any one of embodiments 1-18, wherein the tumor expresses c-Met. 20. The method of any one of claims 1-19, wherein the tumor harbors a MET gene mutation. 5.1.7 BTC Embodiments 1. A method of treating a biliary tract cancer (“BTC”) tumor, comprising administering intravenously every three weeks to a human subject or population of human subjects having said BTC tumor a therapeutically effective amount of 1.6 mg / kg, 2.0 mg / kg, 2.4 mg / kg, 3.0 mg / kg, 3.5 mg / kg, 4.0 mg / kg, or 6.0 mg / kg of an anti-c-Met ADC having the following structure:wherein n is 2, 4, 6, 8, or 10, and wherein Ab is telisotuzumab, thereby treating said BTC tumor. 2. The method of embodiment 1, wherein the BTC tumor is refractory or relapsed. 3. The method of any one of embodiments 1-2, wherein the BTC tumor is histologically or cytologically confirmed locally advanced or metastatic, unresectable intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, or gallbladder cancer with disease progression during or after 1 systemic therapy. 4. The method of any one of embodiments 1-3, wherein administration of the anti-c-Met ADC provides an overall response rate that is greater than greater than 10%, greater than 15%, greater than 20%, 25%, greater than 30%, greater than 35%, greater than 40%, greater than 45%, greater than 50%, greater than 55%, greater than 60%, greater than 65%, greater than 70%, greater than 75%, or greater than 80%. 25 158929154.25. The method of any one of embodiments 1-4, wherein administration of the anti-c-Met ADC achieves a partial response (PR) in the human subject. 6. The method of any one of embodiments 1-4, wherein administration of the anti-c-Met ADC achieves a complete response (CR) in the human subject. 7. The method of any one of embodiments 1-4, wherein administration of the anti-c-Met ADC achieves stable disease (SD) in the subject. 8. The method of any one of embodiments 1-7, wherein n has a value of 2. 9. The method of any one of embodiments 1-7, wherein n has a value of 4. 10. The method of any one of embodiments 1-7, wherein n has a value of 6. 11. The method of any one of embodiments 1-7, wherein n has a value of 8. 12. The method of any one of embodiments 1-7, wherein n has a value of 10. 13. The method of any one of embodiments 1-12, wherein the anti-c-Met ADC is in a pharmaceutical formulation having an average DAR of about 5.4 to about 6.6. 14. The method of any one of embodiments 1-12, wherein the BTC tumor is a histologically or cytologically confirmed locally advanced or metastatic BTC tumor with disease progression during or after 1 systemic therapy, wherein a therapeutically effective amount of 2.4 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to the human subject, wherein the anti-c-Met ADC is in a pharmaceutical formulation having an average drug-antibody ratio (DAR) of about 5.4 to about 6.6, and wherein administration of the anti-c-Met ADC achieves PR in the human patient. 15. The method of any one of embodiments 1-12, wherein the BTC tumor is a histologically or cytologically confirmed locally advanced or metastatic BTC tumor with disease progression during or after 1 systemic therapy, wherein a therapeutically effective amount of 3.0 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to the human subject, wherein the anti-c-Met ADC is in a pharmaceutical formulation having an average drug-antibody ratio (DAR) of about 6, and wherein administration of the anti-c-Met ADC achieves PR in the human patient. 16. The method of any one of embodiments 1-12 and 14, wherein the BTC tumor is a histologically or cytologically confirmed locally advanced or metastatic BTC tumor with disease progression during or after 1 systemic therapy, wherein a therapeutically effective amount of 2.4 mg / kg of the anti-c-Met ADC is administered intravenously 26 158929154.2every three weeks to a plurality of human subjects, wherein the anti-c-Met ADC is in a pharmaceutical formulation having an average drug-antibody ratio (DAR) of about 6, and wherein administration of the anti-c-Met ADC provides an overall response rate that is greater than 25%. 17. The method of any one of embodiments 1-12 and 15, wherein the BTC tumor is a histologically or cytologically confirmed locally advanced or metastatic BTC tumor with disease progression during or after 1 systemic therapy, wherein a therapeutically effective amount of 3.0 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to a plurality of human subjects, wherein the anti-c-Met ADC is in a pharmaceutical formulation having an average drug-antibody ratio (DAR) of about 6, and wherein administration of the anti-c-Met ADC provides an overall response rate that is greater than 25%. 18. The method of embodiment 1, wherein the tumor harbors a MET gene mutation. 19. The method of any one of embodiments 1-18, wherein the tumor expresses c-Met. 20. The method of any one of claims 1-19, wherein the tumor harbors a MET gene mutation. 5.1.8 ESCC Embodiments 1. A method of treating an esophageal squamous cell carcinoma (“ESCC”) tumor, comprising administering intravenously every three weeks to a human subject or population of human subjects having said ESCC tumor a therapeutically effective amount of 1.6 mg / kg, 2.0 mg / kg, 2.4 mg / kg, 3.0 mg / kg, 3.5 mg / kg, 4.0 mg / kg, or 6.0 mg / kg of an anti-c-Met ADC having the following structure:wherein n is 2, 4, 6, 8, or 10, and wherein Ab is telisotuzumab, thereby treating said ESCC tumor. 2. The method of embodiment 1, wherein the ESCC tumor is refractory or relapsed. 27 158929154.23. The method of any one of embodiments 1-2, wherein the ESCC tumor is histologically or cytologically confirmed locally advanced or metastatic with disease progression on no more than 2 prior lines of cytotoxic chemotherapy. 4. The method of any one of embodiments 1-3, wherein administration of the anti-c-Met ADC provides an overall response rate that is greater than greater than 10%, greater than 15%, greater than 20%, 25%, greater than 30%, greater than 35%, greater than 40%, greater than 45%, greater than 50%, greater than 55%, greater than 60%, greater than 65%, greater than 70%, greater than 75%, or greater than 80%. 5. The method of any one of embodiments 1-4, wherein administration of the anti-c-Met ADC achieves a partial response (PR) in the human subject. 6. The method of any one of embodiments 1-4, wherein administration of the anti-c-Met ADC achieves a complete response (CR) in the human subject. 7. The method of any one of embodiments 1-4, wherein administration of the anti-c-Met ADC achieves stable disease (SD) in the subject. 8. The method of any one of embodiments 1-7, wherein n has a value of 2. 9. The method of any one of embodiments 1-7, wherein n has a value of 4. 10. The method of any one of embodiments 1-7, wherein n has a value of 6. 11. The method of any one of embodiments 1-7, wherein n has a value of 8. 12. The method of any one of embodiments 1-7, wherein n has a value of 10. 13. The method of any one of embodiments 1-12, wherein the anti-c-Met ADC is in a pharmaceutical formulation having an average DAR of about 5.4 to about 6.6. 14. The method of any one of embodiments 1-12, wherein the ESCC tumor is histologically or cytologically confirmed locally advanced or metastatic with disease progression on no more than 2 prior lines of cytotoxic chemotherapy, wherein a therapeutically effective amount of 2.4 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to the human subject, wherein the anti-c-Met ADC is in a pharmaceutical formulation having an average drug-antibody ratio (DAR) of about 5.4 to about 6.6, and wherein administration of the anti-c-Met ADC achieves PR in the human patient. 15. The method of any one of embodiments 1-12, wherein the ESCC tumor is histologically or cytologically confirmed locally advanced or metastatic with disease progression on no more than 2 prior lines of cytotoxic chemotherapy, wherein a 28 158929154.2therapeutically effective amount of 3.0 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to the human subject, wherein the anti-c-Met ADC is in a pharmaceutical formulation having an average drug-antibody ratio (DAR) of about 6, and wherein administration of the anti-c-Met ADC achieves PR in the human patient. 16. The method of any one of embodiments 1-12 and 14, wherein the ESCC tumor is histologically or cytologically confirmed locally advanced or metastatic with disease progression on no more than 2 prior lines of cytotoxic chemotherapy, wherein a therapeutically effective amount of 2.4 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to a plurality of human subjects, wherein the anti-c- Met ADC is in a pharmaceutical formulation having an average drug-antibody ratio (DAR) of about 6, and wherein administration of the anti-c-Met ADC provides an overall response rate that is greater than 25%. 17. The method of any one of embodiments 1-12 and 15, wherein the ESCC tumor is histologically or cytologically confirmed locally advanced or metastatic with disease progression on no more than 2 prior lines of cytotoxic chemotherapy, wherein a therapeutically effective amount of 3.0 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to a plurality of human subjects, wherein the anti-c- Met ADC is in a pharmaceutical formulation having an average drug-antibody ratio (DAR) of about 6, and wherein administration of the anti-c-Met ADC provides an overall response rate that is greater than 25%. 18. The method of embodiment 1, wherein the tumor harbors a MET gene mutation. 19. The method of any one of embodiments 1-18, wherein the tumor expresses c-Met. 20. The method of any one of claims 1-19, wherein the tumor harbors a MET gene mutation. 5.1.9 TNBC Embodiments 1. A method of treating a triple-negative breast cancer tumor (“TNBC”) tumor, comprising administering intravenously every three weeks to a human subject or population of human subjects having said TNBC tumor a therapeutically effective amount of 1.6 mg / kg, 2.0 mg / kg, 2.4 mg / kg, 3.0 mg / kg, 3.5 mg / kg, 4.0 mg / kg, or 6.0 mg / kg of an anti-c-Met ADC having the following structure: 29 158929154.2wherein n is 2, 4, 6, 8, or 10, and wherein Ab is telisotuzumab, thereby treating said TNBC tumor. 2. The method of embodiment 1, wherein the TNBC tumor is refractory or relapsed. 3. The method of any one of embodiments 1-2, wherein the TNBC tumor is a histologically or cytologically confirmed locally advanced or metastatic, unresectable TNBC tumor with progression following at least 1 prior line of systemic therapy. 4. The method of any one of embodiments 1-3, wherein administration of the anti-c-Met ADC provides an overall response rate that is greater than greater than 10%, greater than 15%, greater than 20%, 25%, greater than 30%, greater than 35%, greater than 40%, greater than 45%, greater than 50%, greater than 55%, greater than 60%, greater than 65%, greater than 70%, greater than 75%, or greater than 80%. 5. The method of any one of embodiments 1-4, wherein administration of the anti-c-Met ADC achieves a partial response (PR) in the human subject. 6. The method of any one of embodiments 1-4, wherein administration of the anti-c-Met ADC achieves a complete response (CR) in the human subject. 7. The method of any one of embodiments 1-4, wherein administration of the anti-c-Met ADC achieves stable disease (SD) in the subject. 8. The method of any one of embodiments 1-7, wherein n has a value of 2. 9. The method of any one of embodiments 1-7, wherein n has a value of 4. 10. The method of any one of embodiments 1-7, wherein n has a value of 6. 11. The method of any one of embodiments 1-7, wherein n has a value of 8. 12. The method of any one of embodiments 1-7, wherein n has a value of 10. 13. The method of any one of embodiments 1-12, wherein the anti-c-Met ADC is in a pharmaceutical formulation having an average DAR of about 5.4 to about 6.6. 30 158929154.214. The method of any one of embodiments 1-12, wherein the TNBC tumor is a histologically or cytologically confirmed locally advanced or metastatic, unresectable TNBC tumor with progression following at least 1 prior line of systemic therapy, wherein a therapeutically effective amount of 2.4 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to the human subject, wherein the anti- c-Met ADC is in a pharmaceutical formulation having an average drug-antibody ratio (DAR) of about 5.4 to about 6.6, and wherein administration of the anti-c-Met ADC achieves PR in the human patient. 15. The method of any one of embodiments 1-12, wherein the TNBC tumor is a histologically or cytologically confirmed locally advanced or metastatic, unresectable TNBC tumor with progression following at least 1 prior line of systemic therapy, wherein a therapeutically effective amount of 3.0 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to the human subject, wherein the anti- c-Met ADC is in a pharmaceutical formulation having an average drug-antibody ratio (DAR) of about 6, and wherein administration of the anti-c-Met ADC achieves PR in the human patient. 16. The method of any one of embodiments 1-12 and 14, wherein the TNBC tumor is a histologically or cytologically confirmed locally advanced or metastatic, unresectable TNBC tumor with progression following at least 1 prior line of systemic therapy, wherein a therapeutically effective amount of 2.4 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to a plurality of human subjects, wherein the anti-c-Met ADC is in a pharmaceutical formulation having an average drug-antibody ratio (DAR) of about 6, and wherein administration of the anti-c-Met ADC provides an overall response rate that is greater than 25%. 17. The method of any one of embodiments 1-12 and 15, wherein the TNBC tumor is a histologically or cytologically confirmed locally advanced or metastatic, unresectable TNBC tumor with progression following at least 1 prior line of systemic therapy, wherein a therapeutically effective amount of 3.0 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to a plurality of human subjects, wherein the anti-c-Met ADC is in a pharmaceutical formulation having an average drug-antibody ratio (DAR) of about 6, and wherein administration of the anti-c-Met ADC provides an overall response rate that is greater than 25%. 18. The method of embodiment 1, wherein the tumor harbors a MET gene mutation. 19. The method of any one of embodiments 1-18, wherein the tumor expresses c-Met. 31 158929154.220. The method of any one of claims 1-19, wherein the tumor harbors a MET gene mutation. 5.1.10 HR+ / HER2- BC Embodiments 1. A method of treating a hormone receptor-positive / human epidermal growth factor receptor 2-negative breast cancer (“HR+ / HER2- BC”) tumor, comprising administering intravenously every three weeks to a human subject or population of human subjects having said HR+ / HER2- BC tumor a therapeutically effective amount of 1.6 mg / kg, 2.4 mg / kg, 3.0 mg / kg, 3.5 mg / kg, 4.0 mg / kg, or 6.0 mg / kg of an anti-c- Met ADC having the following structure:wherein n is 2, 4, 6, 8, or 10, and wherein Ab is telisotuzumab, thereby treating said HR+ / HER2- BC tumor. 2. The method of embodiment 1, wherein the HR+ / HER2- BC tumor is refractory or relapsed. 3. The method of any one of embodiments 1-2, wherein the HR+ / HER2- BC tumor is a histologically or cytologically confirmed locally advanced or metastatic, unresectable HR+ / HER2- breast cancer tumor with progression following at least 1 prior line of endocrine therapy and a cyclin-dependent kinase (CDK) 4 / 6 inhibitor. 4. The method of any one of embodiments 1-3, wherein administration of the anti-c-Met ADC provides an overall response rate that is greater than greater than 10%, greater than 15%, greater than 20%, 25%, greater than 30%, greater than 35%, greater than 40%, greater than 45%, greater than 50%, greater than 55%, greater than 60%, greater than 65%, greater than 70%, greater than 75%, or greater than 80%. 5. The method of any one of embodiments 1-4, wherein administration of the anti-c-Met ADC achieves a partial response (PR) in the human subject. 32 158929154.26. The method of any one of embodiments 1-4, wherein administration of the anti-c-Met ADC achieves a complete response (CR) in the human subject. 7. The method of any one of embodiments 1-4, wherein administration of the anti-c-Met ADC achieves stable disease (SD) in the subject. 8. The method of any one of embodiments 1-7, wherein n has a value of 2. 9. The method of any one of embodiments 1-7, wherein n has a value of 4. 10. The method of any one of embodiments 1-7, wherein n has a value of 6. 11. The method of any one of embodiments 1-7, wherein n has a value of 8. 12. The method of any one of embodiments 1-7, wherein n has a value of 10. 13. The method of any one of embodiments 1-12, wherein the anti-c-Met ADC is in a pharmaceutical formulation having an average DAR of about 5.4 to about 6.6. 14. The method of any one of embodiments 1-12, wherein the HR+ / HER2- BC tumor is a histologically or cytologically confirmed locally advanced or metastatic, unresectable HR+ / HER2- BC tumor with progression following at least 1 prior line of endocrine therapy and a cyclin-dependent kinase (CDK) 4 / 6 inhibitor, wherein a therapeutically effective amount of 2.4 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to the human subject, wherein the anti-c-Met ADC is in a pharmaceutical formulation having an average drug-antibody ratio (DAR) of about 5.4 to about 6.6, and wherein administration of the anti-c-Met ADC achieves PR in the human patient. 15. The method of any one of embodiments 1-12, wherein the HR+ / HER2- BC tumor is a histologically or cytologically confirmed locally advanced or metastatic, unresectable HR+ / HER2- BC tumor with progression following at least 1 prior line of endocrine therapy and a cyclin-dependent kinase (CDK) 4 / 6 inhibitor, wherein a therapeutically effective amount of 3.0 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to the human subject, wherein the anti-c-Met ADC is in a pharmaceutical formulation having an average drug-antibody ratio (DAR) of about 6, and wherein administration of the anti-c-Met ADC achieves PR in the human patient. 16. The method of any one of embodiments 1-12 and 14, wherein the HR+ / HER2- BC tumor is a histologically or cytologically confirmed locally advanced or metastatic, unresectable HR+ / HER2- BC tumor with progression following at least 1 prior line of endocrine therapy and a cyclin-dependent kinase (CDK) 4 / 6 inhibitor, wherein a 33 158929154.2therapeutically effective amount of 2.4 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to a plurality of human subjects, wherein the anti-c- Met ADC is in a pharmaceutical formulation having an average drug-antibody ratio (DAR) of about 6, and wherein administration of the anti-c-Met ADC provides an overall response rate that is greater than 25%. 17. The method of any one of embodiments 1-12 and 15, wherein the HR+ / HER2- BC tumor is a histologically or cytologically confirmed locally advanced or metastatic, unresectable HR+ / HER2- BC tumor with progression following at least 1 prior line of endocrine therapy and a cyclin-dependent kinase (CDK) 4 / 6 inhibitor, wherein a therapeutically effective amount of 3.0 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to a plurality of human subjects, wherein the anti-c- Met ADC is in a pharmaceutical formulation having an average drug-antibody ratio (DAR) of about 6, and wherein administration of the anti-c-Met ADC provides an overall response rate that is greater than 25%. 18. The method of embodiment 1, wherein the tumor harbors a MET gene mutation. 19. The method of any one of embodiments 1-18, wherein the tumor expresses c-Met. 20. The method of any one of claims 1-19, wherein the tumor harbors a MET gene mutation. 5.1.11 HNSCC Embodiments 1. A method of treating a head and neck squamous cell carcinoma (HNSCC) tumor, comprising administering intravenously every three weeks to a human subject or population of human subjects having said HNSCC tumor a therapeutically effective amount of 1.6 mg / kg, 2.0 mg / kg 2.4 mg / kg, 3.0 mg / kg, 3.5 mg / kg, 4.0 mg / kg, or 6.0 mg / kg of an anti-c-Met ADC having the following structure:34 158929154.2wherein n is 2, 4, 6, 8, or 10, and wherein Ab is telisotuzumab, thereby treating said HNSCC tumor. 2. The method of embodiment 1, wherein the HNSCC tumor is refractory or relapsed. 3. The method of any one of embodiments 1-2, wherein the HNSCC tumor is a histologically or cytologically confirmed locally advanced or recurrent / metastatic, unresectable HNSCC tumor with progression following at least 1 prior line of systemic therapy. 4. The method of any one of embodiments 1-3, wherein administration of the anti-c-Met ADC provides an overall response rate that is greater than greater than 10%, greater than 15%, greater than 20%, 25%, greater than 30%, greater than 35%, greater than 40%, greater than 45%, greater than 50%, greater than 55%, greater than 60%, greater than 65%, greater than 70%, greater than 75%, or greater than 80%. 5. The method of any one of embodiments 1-4, wherein administration of the anti-c-Met ADC achieves a partial response (PR) in the human subject. 6. The method of any one of embodiments 1-4, wherein administration of the anti-c-Met ADC achieves a complete response (CR) in the human subject. 7. The method of any one of embodiments 1-4, wherein administration of the anti-c-Met ADC achieves stable disease (SD) in the subject. 8. The method of any one of embodiments 1-7, wherein n has a value of 2. 9. The method of any one of embodiments 1-7, wherein n has a value of 4. 10. The method of any one of embodiments 1-7, wherein n has a value of 6. 11. The method of any one of embodiments 1-7, wherein n has a value of 8. 12. The method of any one of embodiments 1-7, wherein n has a value of 10. 13. The method of any one of embodiments 1-12, wherein the anti-c-Met ADC is in a pharmaceutical formulation having an average DAR of about 5.4 to about 6.6. 14. The method of any one of embodiments 1-12, wherein the HNSCC tumor is a histologically or cytologically confirmed locally advanced or recurrent / metastatic, unresectable HNSCC tumor with progression following at least 1 prior line of systemic therapy, wherein a therapeutically effective amount of 2.4 mg / kg of the anti- c-Met ADC is administered intravenously every three weeks to the human subject, wherein the anti-c-Met ADC is in a pharmaceutical formulation having an average 35 158929154.2drug-antibody ratio (DAR) of about 5.4 to about 6.6, and wherein administration of the anti-c-Met ADC achieves PR in the human patient. 15. The method of any one of embodiments 1-12, wherein the HNSCC tumor is a histologically or cytologically confirmed locally advanced or recurrent / metastatic, unresectable HNSCC tumor with progression following at least 1 prior line of systemic therapy, wherein a therapeutically effective amount of 3.0 mg / kg of the anti- c-Met ADC is administered intravenously every three weeks to the human subject, wherein the anti-c-Met ADC is in a pharmaceutical formulation having an average drug-antibody ratio (DAR) of about 6, and wherein administration of the anti-c-Met ADC achieves PR in the human patient. 16. The method of any one of embodiments 1-12 and 14, wherein the HNSCC tumor is a histologically or cytologically confirmed locally advanced or recurrent / metastatic, unresectable HNSCC tumor with progression following at least 1 prior line of systemic therapy, wherein a therapeutically effective amount of 2.4 mg / kg of the anti- c-Met ADC is administered intravenously every three weeks to a plurality of human subjects, wherein the anti-c-Met ADC is in a pharmaceutical formulation having an average drug-antibody ratio (DAR) of about 6, and wherein administration of the anti- c-Met ADC provides an overall response rate that is greater than 25%. 17. The method of any one of embodiments 1-12 and 15, wherein the HNSCC tumor is a histologically or cytologically confirmed locally advanced or recurrent / metastatic, unresectable HNSCC tumor with progression following at least 1 prior line of systemic therapy, wherein a therapeutically effective amount of 3.0 mg / kg of the anti- c-Met ADC is administered intravenously every three weeks to a plurality of human subjects, wherein the anti-c-Met ADC is in a pharmaceutical formulation having an average drug-antibody ratio (DAR) of about 6, and wherein administration of the anti- c-Met ADC provides an overall response rate that is greater than 25%. 18. The method of embodiment 1, wherein the tumor harbors a MET gene mutation. 19. The method of any one of embodiments 1-18, wherein the tumor expresses c-Met. 20. The method of any one of claims 1-19, wherein the tumor harbors a MET gene mutation. 36 158929154.25.1.12 MET Gene Mutated Advanced Solid Tumor Embodiments 1. A method of treating a MET gene mutated advanced solid tumor, comprising administering intravenously every three weeks to a human subject or population of human subjects having said MET gene mutated advanced solid tumor a therapeutically effective amount of 1.6 mg / kg, 2.4 mg / kg, 3.0 mg / kg, 3.5 mg / kg, 4.0 mg / kg, or 6.0 mg / kg of an anti-c-Met ADC having the following structure:wherein n is 2, 4, 6, 8, or 10, and wherein Ab is telisotuzumab, thereby treating said MET gene mutated advanced solid tumor. 2. The method of embodiment 1, wherein the MET gene mutated advanced solid tumor is refractory or relapsed. 3. The method of any one of embodiments 1-2, wherein the MET gene mutated advanced solid tumor is an advanced histologically or cytologically confirmed solid tumor harboring MET mutations including mutations in the tyrosine kinase domain, the juxtamembrane region and the extracellular domain, not amenable to surgical resection and with disease progression after at least one prior systemic therapy and / or no satisfactory alternative treatment options. 4. The method of any one of embodiments 1-3, wherein administration of the anti-c-Met ADC provides an overall response rate that is greater than 25%, greater than 30%, greater than 35%, greater than 40%, greater than 45%, greater than 50%, greater than 55%, greater than 60%, greater than 65%, greater than 70%, greater than 75%, or greater than 80%. 5. The method of any one of embodiments 1-4, wherein administration of the anti-c-Met ADC achieves a partial response (PR) in the human subject. 6. The method of any one of embodiments 1-4, wherein administration of the anti-c-Met ADC achieves a complete response (CR) in the human subject. 37 158929154.27. The method of any one of embodiments 1-4, wherein administration of the anti-c-Met ADC achieves stable disease (SD) in the subject. 8. The method of any one of embodiments 1-7, wherein n has a value of 2. 9. The method of any one of embodiments 1-7, wherein n has a value of 4. 10. The method of any one of embodiments 1-7, wherein n has a value of 6. 11. The method of any one of embodiments 1-7, wherein n has a value of 8. 12. The method of any one of embodiments 1-7, wherein n has a value of 10. 13. The method of any one of embodiments 1-12, wherein the anti-c-Met ADC is in a pharmaceutical formulation having an average DAR of about 5.4 to about 6.6. 14. The method of any one of embodiments 1-12, wherein the MET gene mutated advanced solid tumor is an advanced histologically or cytologically confirmed solid tumor harboring MET mutations, not amenable to surgical resection and with disease progression after at least one prior systemic therapy and / or no satisfactory alternative treatment options, wherein a therapeutically effective amount of 2.4 mg / kg of the anti- c-Met ADC is administered intravenously every three weeks to the human subject, wherein the anti-c-Met ADC is in a pharmaceutical formulation having an average drug-antibody ratio (DAR) of about 5.4 to about 6.6, and wherein administration of the anti-c-Met ADC achieves PR in the human patient. 15. The method of any one of embodiments 1-12, wherein the MET gene mutated advanced solid tumor is an advanced histologically or cytologically confirmed solid tumor harboring MET mutations, not amenable to surgical resection and with disease progression after at least one prior systemic therapy and / or no satisfactory alternative treatment options, wherein a therapeutically effective amount of 3.0 mg / kg of the anti- c-Met ADC is administered intravenously every three weeks to the human subject, wherein the anti-c-Met ADC is in a pharmaceutical formulation having an average drug-antibody ratio (DAR) of about 6, and wherein administration of the anti-c-Met ADC achieves PR in the human patient. 16. The method of any one of embodiments 1-12 and 14, wherein MET gene mutated advanced solid tumor is an advanced histologically or cytologically confirmed solid tumor harboring MET mutations, not amenable to surgical resection and with disease progression after at least one prior systemic therapy and / or no satisfactory alternative treatment options, wherein a therapeutically effective amount of 2.4 mg / kg of the anti- 38 158929154.2c-Met ADC is administered intravenously every three weeks to a plurality of human subjects, wherein the anti-c-Met ADC is in a pharmaceutical formulation having an average drug-antibody ratio (DAR) of about 6, and wherein administration of the anti- c-Met ADC provides an overall response rate that is greater than 25%. 17. The method of any one of embodiments 1-12 and 15, wherein the MET gene mutated advanced solid tumor is an advanced histologically or cytologically confirmed solid tumor harboring MET mutations, not amenable to surgical resection and with disease progression after at least one prior systemic therapy and / or no satisfactory alternative treatment options, wherein a therapeutically effective amount of 3.0 mg / kg of the anti- c-Met ADC is administered intravenously every three weeks to a plurality of human subjects, wherein the anti-c-Met ADC is in a pharmaceutical formulation having an average drug-antibody ratio (DAR) of about 6, and wherein administration of the anti- c-Met ADC provides an overall response rate that is greater than 25%. 18. The method of embodiment 1, wherein the tumor harbors a MET gene mutation. 19. The method of any one of embodiments 1-18, wherein the tumor expresses c-Met. 6. BRIEF DESCRIPTION OF THE FIGURES

[0086] FIG.1: Reduced reversed phase liquid chromatographs of the ADC1 composition.

[0087] FIG.2: A deconvoluted mass spectrum of the ADC1 composition.

[0088] FIG.3: A dose escalation scheme.

[0089] FIG.4: A clinical trial design for monotherapy dose expansion.

[0090] FIGS.5A and 5B: PK profiles of the ADC1 composition (FIG.5A) and Top1i (FIG. 5B).

[0091] FIGS.6A and 6B: Percentage change in target lesion measurement from baseline over time in all patients (FIG.6A; N=57) and patients with CRC (FIG.6B; N=27)

[0092] FIGS.7A-7D show representative cytoplasmic staining intensities for c-Met on non- squamous NSCLC. SP44 OptiView IHC Cytoplasmic Staining Intensities (20X) of IHC score of 0 (FIG.7A); 1+ (FIG.7B); 2+ (FIG.7C); and 3+ (FIG.7D).

[0093] FIGS.8A-8D show representative membranous staining intensities for c-Met on non- squamous NSCLC. SP44 OptiView IHC Membranous Staining Intensities 20X of IHC score of 0 (FIG.8A); 1+ (FIG.8B); 2+ (FIG.8C); and 3+ (FIG.8D). 39 158929154.2

[0094] FIGS.9A1-9C3, FIGS.9B1-9B3, and FIGS.9C1-9C3 show representative membranous staining intensities for c-Met on non-squamous NSCLC. SP44 OptiView IHC Membranous Staining Intensities 20X of c-Met Negative (FIGS.9A1-9A3); c-Met Positive (FIGS.9B1-9B3); and c-Met High (FIGS.9C1-9C3).

[0095] FIG.10 shows distribution of SP44 UltraView and OptiView IHC at 3+ intensity staining on a commercial cohort of NSCLC.

[0096] FIG.11 shows that ≥25% 3+ cutoff for SP44 OptiView, selects similar patient population as SP44 Ultraview. Abbreviations shown in FIG.5 and determination of the values in the table are as follow: PPA (positive percent agreement): # oV positive uV positive / Total uV positive; NPA (Negative percent agreement): # oV negative uV negative / Total uV negative; OPA (Overall percent agreement):# oV positive uV positive + #oV negative uV negative / Total number of samples tested; PPV (Positive predictive value): # of oV positive uV positive / total # of oV positive; NPV (Negative predictive value): # of oV negative uV negative / Total oV negative. %BOR represents the percent best overall response.

[0097] FIG.12 shows that ≥50% 3+ cutoff for SP44 OptiView, selects similar patient population as SP44 Ultraview. Abbreviations shown in FIG.12 and determination of the values in the table are as follow: PPA (positive percent agreement): # oV positive uV positive / Total uV positive; NPA (Negative percent agreement): # oV negative uV negative / Total uV negative; OPA (Overall percent agreement):# oV positive uV positive + #oV negative uV negative / Total number of samples tested; PPV (Positive predictive value): # of oV positive uV positive / total # of oV positive; NPV (Negative predictive value): # of oV negative uV negative / Total oV negative. %BOR represents the percent best overall response.

[0098] FIGS.13A and 13B: Percentage change in target lesion measurement from baseline over time in patients with EGFR-wt non-squamous NSCLC (part 2i), EGFR-mu non- squamous NSCLC (part 2ii) and squamous NSCLC (part 2i); percentage change in target lesion measurement from baseline over time in patients with EGFR-wt non-squamous NSCLC (part 2i).

[0099] FIGS.14A and 14B : Percentage change in target lesion measurement from baseline over time in patients with GEA.

[0100] FIGS.15A – 15B: Percentage change in target lesion measurement from baseline over time in patients with CRC in Part 1 (FIG.15A) and patients with CRC in Part 4 (FIG. 15B). 40 158929154.2

[0101] FIG.16: Percentage change in target lesion measurement from baseline over time in patients with MET Amplified tumors (N=27). 7. DETAILED DESCRIPTION

[0102] Provided herein are methods of treating a solid tumor by administering to a human subject having said solid tumor a therapeutically effective amount of an anti-c-Met ADC. A therapeutically effective amount of an anti-c-Met ADC is an amount sufficient to result in stable disease, partial response, or a complete response in the subject per RECIST v1.1, and / or increase in overall survival. In preferred embodiments, the anti-c-Met ADC is ADC1 (see Section 6.2).

[0103] Solid tumors treatable by the methods described herein include, but are not limited to, a non-small cell lung cancer (“NSCLC”) tumor, a gastroesophageal adenocarcinoma (“GEA”) tumor, a colorectal cancer (“CRC”) tumor, a MET amplified advanced solid tumor, a hepatocellular carcinoma (“HCC”) tumor, a biliary tract cancer (“BTC”) tumor, a pancreatic ductal adenocarcinoma (“PDAC”) tumor, an esophageal squamous cell carcinoma (ESCC) tumor, a triple-negative (“TN”) breast cancer (“BC”) tumor, a hormone receptor- positive / human epidermal growth factor receptor 2 negative breast cancer tumor (“HR+ / HER2- BC”), a head and neck squamous cell carcinoma (“HNSCC”) tumor or a MET gene mutated tumor. The methods for treating comprise administering to a human subject having said solid tumor a therapeutically effective amount of an anti-c-Met ADC. A therapeutically effective amount of an anti-c-Met ADC is an amount sufficient to result in stable disease, partial response, or a complete response in the subject per RECIST v1.1, and / or increase in overall survival. In preferred embodiments, the anti-c-Met ADC is ADC1 (see Section 6.2). In such preferred embodiment, ADC1 is administered once every three (3) weeks at a dose of 1.6 mg / kg, 2.4 mg / kg, 3.0 mg / kg, 3.5 mg / kg, 4.0 mg / kg, or 6.0 mg / kg. 7.1 Definitions

[0104] As used in this disclosure, the singular forms “a”, “an” and “the” include plural referents unless the context clearly dictates otherwise. The terms “a” (or “an”), as well as the terms “one or more,” and “at least one” can be used interchangeably herein unless the context clearly dictates otherwise.

[0105] The term “and / or” as used in a phrase such as “A and / or B” herein is intended to mean “A and B”, “A or B”, “A” or “B”. 41 158929154.2

[0106] As used in this disclosure and unless otherwise specified, the terms “about” and “approximately” generally refer to a range of numbers that one of skill in the art would consider equivalent to the recited value (i.e., having the same function or result). In many instances, the terms “about” and “approximately” may include numbers that are rounded to the nearest significant figure. In specific embodiments, the terms “about” and “approximately” shall be construed so as to allow normal variation as judged by a person of ordinary skill in the art, such as, for example, a variation within 20% or 10% or 5%. In specific embodiments, the terms “about” and “approximately” encompass the exact value recited. Unless the context clearly dictates otherwise, all numerical values provided herein are modified by the term about.

[0107] The terms “patient” and “subject” are used herein interchangeably and refer to a human. In a specific embodiment, the subject is a human adult (i.e., at least 18 years old).

[0108] Unless the context requires otherwise, the terms “comprise,” “comprises,” and “comprising” are used on the basis and clear understanding that they are to be interpreted inclusively, rather than exclusively, such that they indicate the inclusion of the recited feature but without excluding one or more other such features. However, it is understood that wherever aspects and embodiments are described herein with the language “comprise” (or “comprises” or “comprising”), otherwise analogous aspects described in terms of “consist of” (or “consists of” or “consisting of”) and / or “consist essentially of” (or “consists essentially of” or “consisting essentially of”) are also provided.

[0109] The term “a therapeutically effective amount” of an ADC used herein refers to an amount of an ADC sufficient to result in stable disease, partial response, or a complete response in the subject per RECIST v1.1, and / or increase in overall survival. RECIST v1.1 is published in New response evaluation criteria in solid tumors: Revised RECIST guideline (version 1.1), Eur Journal of Cancer 45 (2009) 228 – 247, which is incorporated herein in its entirety as a reference. “Complete Response (CR)” refers to disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. “Partial Response (PR)” refers to at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. “Progressive Disease (PD)” refers to at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is 42 158929154.2also considered progression). “Stable Disease (SD)” refers to neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. 7.2 Anti-c-Met ADC and ADC1

[0110] As described herein, the anti-c-Met ADC has the following structure:

[0111] wherein n is 2, 4, 6, 8, or 10, and wherein Ab is an IgG1 anti-c-Met antibody comprising a heavy chain variable region comprising the amino acid sequence shown as SEQ ID NO: 7: QVQLVQSGAEVKKPGASVKVSCKASGYIFTAYTMHWVRQAPGQGLEWMGWIKPN NGLANYAQKFQGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARSEITTEFDYWGQ GTLVTVSS (SEQ ID NO: 7); and a light chain variable region comprising the amino acid sequence shown as SEQ ID NO: 8: DIVMTQSPDSLAVSLGERATINCKSSESVDSYANSFLHWYQQKPGQPPKLLIYRASTR ESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQSKEDPLTFGGGTKVEIK (SEQ ID NO: 8).

[0112] In a preferred embodiment, Ab is telisotuzumab. In such a preferred embodiment, the anti-c-Met ADC is referred to as ADC1. Telisotuzumab is a humanized recombinant IgG1κ antibody (disclosed as 224G11 [TH7 Hz3] in U.S. Patent No.8,741,290) that targets a unique epitope of c-Met located within the immunoglobulin-plexin-transcription factor homology (IPT) domain 1, resulting in blockade of both HGF-dependent and HGF-independent c-Met signaling. 43 158929154.2

[0113] Telisotuzumab comprises a heavy chain comprising the amino acid sequence shown as SEQ ID NO: 9 (constant regions are bold; CDRs as defined under the IMGT nomenclature are underlined (disclosed as SEQ ID NOS: 1-3, respectively, in order of appearance)): QVQLVQSGAE VKKPGASVKV SCKASGYIFT AYTMHWVRQA PGQGLEWMGW 050 IKPNNGLANY AQKFQGRVTM TRDTSISTAY MELSRLRSDD TAVYYCARSE 100 ITTEFDYWGQ GTLVTVSSAS TKGPSVFPLA PSSKSTSGGT AALGCLVKDY 150 FPEPVTVSWN SGALTSGVHT FPAVLQSSGL YSLSSVVTVP SSSLGTQTYI 200 CNVNHKPSNT KVDKRVEPKS CDCHCPPCPA PELLGGPSVF LFPPKPKDTL 250 MISRTPEVTC VVVDVSHEDP EVKFNWYVDG VEVHNAKTKP REEQYNSTYR 300 VVSVLTVLHQ DWLNGKEYKC KVSNKALPAP IEKTISKAKG QPREPQVYTL 350 PPSREEMTKN QVSLTCLVKG FYPSDIAVEW ESNGQPENNY KTTPPVLDSD 400 GSFFLYSKLT VDKSRWQQGN VFSCSVMHEA LHNHYTQKSL SLSPG 445 (full-length sequence disclosed as SEQ ID NO: 9)

[0114] In embodiments, the Ab comprises heavy chains of SEQ ID NO: 9 with the addition of a C-terminal lysine (K) residue.

[0115] and a light chain comprising the amino acid sequence shown as SEQ ID NO: 10 (CDR sequences as defined under the IMGT nomenclature are underlined (disclosed as SEQ ID NOS: 4-6, respectively, in order of appearance)): DIVMTQSPDS LAVSLGERAT INCKSSESVD SYANSFLHWY QQKPGQPPKL 050 LIYRASTRES GVPDRFSGSG SGTDFTLTIS SLQAEDVAVY YCQQSKEDPL 100 TFGGGTKVEI KRTVAAPSVF IFPPSDEQLK SGTASVVCLL NNFYPREAKV 150 QWKVDNALQS GNSQESVTEQ DSKDSTYSLS STLTLSKADY EKHKVYACEV 200 THQGLSSPVT KSFNRGEC 218 (full-length sequence disclosed as SEQ ID NO: 10).

[0116] The heavy chain of telisotuzumab is encoded by the following nucleotide sequence (full-length sequence disclosed as SEQ ID NO: 11): ATGGGATGGTCTTGGATCTTTCTGCTGTTTCTGTCTGGTACTGCTGGTGTGC TGAGCcaggtccagctggtgcaatccggcgcagaggtgaagaagccaggcgcttccgtgaaggtgagctgtaaggcctctgg ctacatcttcacagcatacaccatgcactgggtgaggcaagctcctgggcagggactggagtggatgggatggattaaacccaacaa 44 158929154.2tgggctggccaactacgcccagaaattccagggtagggtcactatgacaagggataccagcatcagcaccgcatatatggagctgag caggctgaggtctgacgacactgctgtctattattgcgccaggagcgaaattacaacagaattcgattactgggggcagggcaccctg gtgaccgtgtcctctgccagcaccaagggcccaagcgtgttccccctggcccccagcagcaagagcaccagcggcggcacag ccgccctgggctgcctggtgaaggactacttccccgagcccgtgaccgtgtcctggaacagcggagccctcacttctggagttc ataccttcccagcagtattgcagagcagtggcctgtattcactgtcttccgtcgtaacagttccatcctccagcctcgggacaca gacttacatttgtaacgtgaatcacaagcctagcaacaccaaggtcgacaagagagttgaaccaaagagttgtgattgccact gtcctccctgcccagctcctgagctgcttggcggtcccagtgtcttcttgtttccccctaaacccaaagacaccctgatgatctca aggactcccgaggtgacatgcgtggtggtggatgtgtctcatgaggacccagaggtgaagttcaactggtacgtggacggcgt ggaggtgcacaacgccaagaccaagcccagagaggagcagtacaacagcacctacagggtggtgtccgtgctgaccgtgct gcaccaggactggctgaacggcaaggagtacaagtgtaaggtgtccaacaaggccctgccagccccaatcgaaaagaccat cagcaaggccaagggccagccaagagagccccaggtgtacaccctgccacccagcagggaggagatgaccaagaaccag gtgtccctgacctgtctggtgaagggcttctacccaagcgacatcgccgtggagtgggagagcaacggccagcccgagaaca actacaagaccacccccccagtgctggacagcgacggcagcttcttcctgtacagcaagctgaccgtggacaagagcagatg gcagcagggcaacgtgttcagctgctccgtgatgcacgaggccctgcacaaccactacacccagaagagcctgagcctgtcc ccaggctga (SEQ ID NO: 11)

[0117] Secretion signal peptide in bold CAPITAL letters; includes final stop codon (TGA); constant region is bold; CDRs are underlined (CDR sequences disclosed as SEQ ID NOS: 12- 14, respectively, in order of appearance)

[0118] The light chain of telisotuzumab is encoded by the following nucleotide sequence (full-length sequence disclosed as SEQ ID NO: 15): ATGGAAACTGATACACTGCTGCTGTGGGTCCTGCTGCTGTGGGTCCCTGGA AGCACAGGGgacattgtgatgacccagtctcccgatagcctggccgtgtccctgggcgagagggctaccatcaactgtaaa agctccgaatctgtggactcttacgcaaacagctttctgcactggtatcagcaaaagccaggccaacctccaaagctgctgatttacag ggcttctaccagggagagcggcgtgcccgataggttcagcggatctggcagcggcaccgactttacactgaccatctccagcctgca ggccgaagatgtggcagtctattactgccagcagtccaaggaggaccccctgactttcgggggtggtactaaagtggagatcaagcg tacggtggccgctcccagcgtgttcatcttccccccaagcgacgagcagctgaagagcggcaccgccagcgtggtgtgtctgc tgaacaacttctaccccagggaggccaaggtgcagtggaaggtggacaacgccctgcagagcggcaacagccaggagagc gtcaccgagcaggacagcaaggactccacctacagcctgagcagcaccctgaccctgagcaaggccgactacgagaagca caaggtgtacgcctgtgaggtgacccaccagggcctgtccagccccgtgaccaagagcttcaacaggggcgagtgctga (SEQ ID NO: 15) 45 158929154.2

[0119] Secretion signal peptide in bold CAPITAL letters; includes final stop codon (TGA); constant region is bold; CDRs are underlined (CDR sequences disclosed as SEQ ID NOS: 16- 18, respectively, in order of appearance).

[0120] In specific embodiments, conjugation of the linker-drug to telisotuzumab is via a linkage formed with a sulfhydryl group of a cysteine residue of the antibody.

[0121] In specific embodiments, the number (n) of drugs attached to telisotuzumab in ADC1 is 2, 4, 6, 8 or 10. In an embodiment, ADC1 is a composition comprising a plurality of ADC1 species with two or more different values of n. In some embodiments, the composition of ADC1 has an average drug-antibody ratio (DAR) of about 5 to about 7, about 5.4 to about 6.6, or of about 5.8, about 5.9, about 6.0, about 6.1, or about 6.2. In some embodiments, the composition of ADC1 has an average of six molecules of the topoisomerase 1 inhibitor (Top1i) conjugated to telisotuzumab. In some embodiments, the predominant species of ADC1 in the composition has n = 6. In some embodiments, ADC1 has an average DAR of about 6. 7.3 Methods of Use 7.3.1 Non-Small Cell Lung Cancer NSCLC

[0122] In one aspect, provided herein is a method of treating a non-small cell lung cancer (“NSCLC”) tumor, comprising administering to a human subject or population of human subjects having said NSCLC tumor a therapeutically effective amount of an anti-c-Met antibody drug conjugate (ADC), wherein the anti-c-Met ADC has the following structure:

[0123] wherein n is 2, 4, 6, 8, or 10, and wherein Ab is telisotuzumab (such an anti-c-Met ADC is also referred to in this disclosure as ADC1), thereby treating said NSCLC tumor.

[0124] In a preferred embodiment, ADC1 is administered to the human patient once every three (3) weeks at a dose of 1.6 mg / kg, 2.4 mg / kg, 3.0 mg / kg, 3.5 mg / kg, 4.0 mg / kg, or 6.0 46 158929154.2mg / kg. In a preferred embodiment, ADC1 is administered parenterally. In a preferred embodiment, the parenteral administration is intravenous administration. In a preferred embodiment, ADC1 is administered once every three weeks until disease progression, withdrawal of consent, or unacceptable toxicity.

[0125] In certain embodiments, the NSCLC tumor is at an advanced stage. In certain embodiments, the NSCLC tumor is a relapsed NSCLC tumor. In certain embodiments, the NSCLC tumor is a refractory or relapsed NSCLC tumor.

[0126] In certain embodiments, the NSCLC tumor has progressed after treatment with at least platinum-based chemotherapy and an immune checkpoint inhibitor and / or appropriate applicable targeted therapy.

[0127] In certain embodiments, the NSCLC tumor has progressed after treatment with at least platinum-based chemotherapy doublet and / or tyrosine kinase inhibitor(s).

[0128] In certain embodiments, the human subject has had no more than 2 lines of prior cytotoxic chemotherapy excluding adjuvant therapy.

[0129] In certain embodiments, the NSCLC tumor is an advanced NSCLC that is not amenable to surgical resection or other approved therapeutic option(s) (including immunotherapy(ies)) that have demonstrated clinical benefit.

[0130] In certain embodiments, the NSCLC tumor is non-squamous NSCLC. In certain embodiments, the NSCLC tumor is squamous NSCLC.

[0131] In certain embodiments, the NSCLC tumor is an advanced solid tumor that has progressed on all standard of care therapy(ies) and is not amenable to surgical resection or other approved therapeutic option(s) that have demonstrated clinical benefit.

[0132] In various embodiments, the NSCLC tumor expresses c-Met. In embodiments, only subjects with a NSCLC tumor that expresses c-Met are treated, and subjects with tumors that do not express c-Met are excluded from treatment. In certain embodiments, the c-Met expressing NSCLC tumor is histologically or cytologically confirmed locally advanced or metastatic, unresectable NSCLC with progression following at least 1 prior line of systemic therapy administered in the advanced / metastatic setting.

[0133] In various embodiments, subjects having a NSCLC tumor are treated without knowledge or assessment of NSCLC tumor c-Met expression. 47 158929154.2

[0134] In some embodiments, the NSCLC tumor is treated without regard to its EGFR status, i.e., without regard as to whether it expresses wildtype epidermal growth factor receptor (EGFR-wt) or mutated EGFR (EGFR-mu).

[0135] In some embodiments, the NSCLC tumor expresses wildtype epidermal growth factor receptor (EGFR-wt). In certain embodiments, the NSCLC tumor expresses both c-Met and EGFR-wt.

[0136] In other embodiments, the NSCLC tumor expresses mutated EGFR (EGFR-mu). In certain embodiments, the NSCLC tumor expresses both c-Met and EGFR-mu.

[0137] In some embodiments, the EGFR status (wild-type or mutant) of the NSCLC is detected by an FDA-approved test. One such test uses real-time polymerase chain reaction (PCR) to identify at least 42 mutations in exons 18, 19, 20 and 21 of the EGFR gene. The test has been clinically validated in multiple clinical trials as a companion diagnostic (CDx) for both first- and second-line EGFR TKI therapy in patients with advanced NSCLC (Heeke et al., (2019) Clinical Lung Cancer 21 (1): 56-65). Next generation sequencing (NGS) can also be used to detect EGFR mutations. A number of companies have FDA approved CDx assays to detect EGFR mutations, including Foundation One CDx, Thermo Fisher Oncomine NSCLC and Guardant 360CDx. See also Ding et al., (2019) Thoracic Cancer 10: 1879-1884 discussing the use of the Thermo Fisher Oncomine NSCLC assay.

[0138] In specific embodiments, the NSCLC tumor has progressed after treatment with at least platinum-based chemotherapy and an immune checkpoint inhibitor and / or appropriate applicable targeted therapy. In specific embodiments, the NSCLC tumor has progressed after treatment with at least platinum-based chemotherapy doublet and / or tyrosine kinase inhibitor(s). In specific embodiments, the human subject has had no more than 2 lines of prior cytotoxic chemotherapy excluding adjuvant therapy. In specific embodiments, the NSCLC tumor is an advanced NSCLC that is not amenable to surgical resection or other approved therapeutic option(s) (including immunotherapy(ies)) that have demonstrated clinical benefit.

[0139] In specific embodiments, the NSCLC tumor is a tumor with EGFR-wt-expression (e.g., an advanced non-squamous NSCLC tumor with EGFR-wt-expression). In embodiments, only subjects having an NSCLC tumor with EGFR-wt-expression (e.g., an advanced non-squamous NSCLC tumor with EGFR-wt-expression) are treated, and subjects with other NSCLC tumors, e.g., squamous NSCLC or tumors with EGFR-mu-expression are excluded from treatment. In embodiments, only subjects having an NSCLC tumor with 48 158929154.2EGFR-mu-expression (e.g., an advanced non-squamous NSCLC tumor with EGFR-mu- expression) are treated, and subjects with other NSCLC tumors, e.g., squamous NSCLC or tumors with EGFR-wt-expression are excluded from treatment. In specific embodiments, the NSCLC tumor has progressed after treatment with at least platinum-based chemotherapy and an immune checkpoint inhibitor and / or appropriate applicable targeted therapy. In specific embodiments, the human subject has had no more than 2 lines of prior cytotoxic chemotherapy excluding adjuvant therapy. In specific embodiments, the NSCLC tumor is an advanced NSCLC that is not amenable to surgical resection or other approved therapeutic option(s) (including immunotherapy(ies)) that have demonstrated clinical benefit.

[0140] In specific embodiments, the NSCLC tumor is a squamous NSCLC tumor. In specific embodiments, the squamous NSCLC tumor has progressed after treatment with at least platinum-based chemotherapy and an immune checkpoint inhibitor and / or appropriate applicable targeted therapy. In specific embodiments, the human subject has had no more than 2 lines of prior cytotoxic chemotherapy excluding adjuvant therapy. In specific embodiments, the NSCLC tumor is an advanced squamous NSCLC that is not amenable to surgical resection or other approved therapeutic option(s) (including immunotherapy(ies)) that have demonstrated clinical benefit.

[0141] In specific embodiments, the NSCLC tumor is a refractory or relapsed NSCLC tumor, a therapeutically effective amount of 2.4 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to the human subject, the anti-c-Met ADC has an average DAR of about 6, and administration of the anti-c-Met ADC achieves PR in the human subject. In specific embodiments, the NSCLC tumor is a refractory or relapsed NSCLC tumor, a therapeutically effective amount of 3.0 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to the human subject, the anti-c-Met ADC has an average DAR of about 6, and administration of the anti-c-Met ADC achieves PR in the human subject. In specific embodiments, the NSCLC tumor is a refractory or relapsed NSCLC tumor, a therapeutically effective amount of 2.4 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to the human subject, the anti-c-Met ADC has an average DAR of about 6, and administration of the anti-c-Met ADC provides an overall response rate that is greater than 25%. In specific embodiments, the NSCLC tumor is a refractory or relapsed NSCLC tumor, a therapeutically effective amount of 3.0 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to the human subject, the 49 158929154.2anti-c-Met ADC has an average DAR of about 6, and administration of the anti-c-Met ADC provides an overall response rate that is greater than 25%.

[0142] In embodiments, subjects having EGFR-wt non-squamous (NSQ) NSCLC treated according to the methods of this section experience an overall response rate (“ORR”) of 30% or higher, for example 40%, 50% or higher. In embodiments, the treatment of a population of selected subjects having EGFR-wt NSQ NSCLC tumors is with a regimen that results in an ORR of 30%, 40%, 50% or higher when subjects that 1) meet the eligibility criteria of section 8.2.1 and 2) have EGFR-wt NSQ NSCLC tumors are treated.

[0143] In embodiments, subjects having EGFR-wt NSQ NSCLC treated according to the methods of this section experience a clinical benefit rate at 12 weeks (CBR12) of 50% or higher, for example 60%, 70% or higher. In embodiments, the treatment of a population of selected subjects having EGFR-wt NSQ NSCLC tumors is with a regimen that results in a CBR12 of 50% or higher, for example 60%, 70% or higher when subjects that 1) meet the eligibility criteria of section 8.2.1 and 2) have EGFR-wt NSQ NSCLC tumors are treated.

[0144] In embodiments, subjects having EGFR-wt NSQ NSCLC treated according to the methods of this section experience a clinical benefit rate (“CBR”) of 60% or higher, for example 70% or 80% or higher. In embodiments, subjects having EGFR-wt NSQ NSCLC treated according to the methods of this section experience a CBR of 60% or higher, for example 70% or 80% or higher.

[0145] In embodiments, subjects having EGFR-mu NSQ NSCLC treated according to the methods of this section experience an ORR of 30% or higher, for example 40%, 50% or higher. In embodiments, the treatment of a population of selected subjects having EGFR-mu NSQ NSCLC tumors is with a regimen that results in an ORR of 30% or higher, for example 40%, 50% or higher when subjects that 1) meet the eligibility criteria of section 8.2.1 and 2) have EGFR-mu NSQ NSCLC tumors are treated.

[0146] In embodiments, subjects having squamous NSCLC treated according to the methods of this section experience a CBR of 20% or higher, for example 25% or 30% or higher. In embodiments, the treatment of a population of selected subjects having squamous NSCLC tumors is with a regimen that results in an ORR 20% or higher, for example 25% or 30% or higher when subjects that 1) meet the eligibility criteria of section 8.2.1 and 2) have squamous NSCLC tumors are treated. 50 158929154.2

[0147] In one embodiment, the method of treatment comprises the steps of determining the level of c-Met expression within the NSCLC tumor by performing c-Met immunohistochemistry (IHC) on tumor tissue (i.e., obtained from a biopsy, resection or cytology sample; the tumor tissue can be archival tumor tissue or fresh tumor tissue) from the subject. In embodiments, subjects having a “positive c-Met expression level for NSCLC” are treated, with positive c-Met expression level for NSCLC defined by ≥50% of neoplastic cells from tumor tissue assessed by c-Met IHC having at least 2+ membrane or membrane + cytoplasm staining (≥50% 2+). In embodiments, subjects having a “positive c-Met expression level for NSCLC” are treated, with positive c-Met expression level for NSCLC defined by ≥75% of neoplastic cells from tumor tissue assessed by c-Met IHC having at least 2+ membrane or membrane + cytoplasm staining (≥75% 2+). In embodiments, subjects having a “positive c-Met expression level for NSCLC” are treated, with positive c-Met expression level for NSCLC defined by ≥10% of neoplastic cells from tumor tissue assessed by c-Met IHC having at least 3+ membrane or membrane + cytoplasm staining (≥10% 3+). In embodiments, subjects having a “positive c-Met expression level for NSCLC” are treated, with positive c-Met expression level for NSCLC defined by ≥25 of neoplastic cells from tumor tissue assessed by c-Met IHC having at least 3+ membrane or membrane + cytoplasm staining (≥25% 3+). In embodiments, subjects having a “positive c-Met expression level for NSCLC” are treated, with positive c-Met expression level for NSCLC defined by ≥50% of neoplastic cells from tumor tissue assessed by c-Met IHC having at least 3+ membrane or membrane + cytoplasm staining (≥50% 3+).

[0148] In embodiments, only those subjects having a positive c-Met expression level for NSCLC are treated. In embodiments, subjects who do not exhibit positive c-Met expression level for NSCLC are excluded from treatment. In embodiments, a population of subjects having NSCLC tumors are evaluated for NSCLC tumor c-Met expression and those exhibiting positive c-Met expression level for NSCLC are selected for treatment, and those not exhibiting positive c-Met expression level for NSCLC are excluded from treatment. The level of c-Met expression of the NSCLC tumor is taken to be that of its sampled tissue, as determined by c-Met IHC. In some embodiments, the c-Met IHC is performed according to the c-Met Staining Protocol.

[0149] In embodiments, treatment of selected subjects having EGFR-wt NSQ NSCLC tumors that exhibit a positive c-Met expression level for NSCLC of ≥50% 2+ results in an ORR of 40%, 45%, 48% or higher. In embodiments, the treatment of a population of selected 51 158929154.2subjects having EGFR-wt NSQ NSCLC tumors that exhibit a positive c-Met expression level for NSCLC of ≥50% 2+ is with a regimen that results in an ORR of 40%, 45%, 48% or higher when subjects that 1) meet the eligibility criteria of section 8.2.1 and 2) have EGFR- wt NSQ NSCLC tumors that exhibit a positive c-Met expression level for NSCLC of ≥50% 2+ are treated.

[0150] In embodiments, treatment of selected subjects having EGFR-wt NSQ NSCLC tumors that exhibit a positive c-Met expression level for NSCLC of ≥10% 3+ results in an ORR of 55%, 60%, 64% or higher. In embodiments, the treatment of a population of selected subjects having EGFR-wt NSQ NSCLC tumors that exhibit a positive c-Met expression level for NSCLC of ≥10% 3+ is with a regimen that results in an ORR of 55%, 60%, 64% or higher when subjects that 1) meet the eligibility criteria of section 8.2.1 and 2) have EGFR- wt NSCLC tumors that exhibit a positive c-Met expression level for NSQ NSCLC of ≥10% 3+ are treated.

[0151] In embodiments, treatment of selected subjects having NSQ EGFR-wt NSCLC tumors that exhibit a positive c-Met expression level for NSCLC of ≥25% 3+ results in an ORR of 50%, 55%, 60% or higher. In embodiments, the treatment of a population of selected subjects having EGFR-wt NSCLC tumors that exhibit a positive c-Met expression level for NSCLC of ≥25% 3+ is with a regimen that results in an ORR of 50%, 55%, 60% or higher when subjects that 1) meet the eligibility criteria of section 8.2.1 and 2) have EGFR-wt NSQ NSCLC tumors that exhibit a positive c-Met expression level for NSQ NSCLC of ≥25% 3+ are treated.

[0152] In embodiments, treatment of selected subjects having EGFR-wt NSQ NSCLC tumors that exhibit a positive c-Met expression level for NSCLC of ≥50% 3+ results in an ORR of 65%, 70%, 75% or higher. In embodiments, the treatment of a population of selected subjects having EGFR-wt NSQ NSCLC tumors that exhibit a positive c-Met expression level for NSCLC of ≥50% 3+ is with a regimen that results in an ORR of 65%, 70%, 75% or higher when subjects that 1) meet the eligibility criteria of section 8.2.1 and 2) have EGFR- wt NSQ NSCLC tumors that exhibit a positive c-Met expression level for NSCLC of ≥50% 3+ are treated.

[0153] In embodiments, treatment of selected subjects having EGFR-wt NSQ NSCLC tumors that exhibit a positive c-Met expression level for NSCLC of ≥50% 2+ and <25% 3+ results in an ORR of 35%, 40%, 41% or higher. In embodiments, the treatment of a 52 158929154.2population of selected subjects having EGFR-wt NSQ NSCLC tumors that exhibit a positive c-Met expression level for NSCLC of ≥50% 2+ is with a regimen that results in an ORR of 35%, 40%, 41% or higher when subjects that 1) meet the eligibility criteria of section 8.2.1 and 2) have EGFR-wt NSQ NSCLC tumors that exhibit a positive c-Met expression level for NSCLC of ≥50% 2+ are treated.

[0154] In embodiments, treatment of selected subjects having EGFR-mu NSQ NSCLC tumors that exhibit a positive c-Met expression level for NSCLC of ≥25% 3+ results in an ORR of 35%, 40%, 45% or higher. In embodiments, the treatment of a population of selected subjects having EGFR-mu NSQ NSCLC tumors that exhibit a positive c-Met expression level for NSCLC of ≥25% 3+ is with a regimen that results in an ORR of 35%, 40%, 45% or higher when subjects that 1) meet the eligibility criteria of section 8.2.1 and 2) have EGFR- mu NSQ NSCLC tumors that exhibit a positive c-Met expression level for NSCLC of ≥25% 3+ are treated.

[0155] In embodiments, treatment of selected subjects having EGFR-mu NSQ NSCLC tumors that exhibit a positive c-Met expression level for NSCLC of ≥50% 2+ results in an ORR of 35%, 40%, 45% or higher. In embodiments, the treatment of a population of selected subjects having EGFR-mu NSQ NSCLC tumors that exhibit a positive c-Met expression level for NSCLC of ≥50% 2+ is with a regimen that results in an ORR of 35%, 40%, 45% or higher when subjects that 1) meet the eligibility criteria of section 8.2.1 and 2) have EGFR- mu NSQ NSCLC tumors that exhibit a positive c-Met expression level for NSCLC of ≥50% 2+ are treated.

[0156] In embodiments, treatment of selected subjects having EGFR-mu NSQ NSCLC tumors that exhibit a positive c-Met expression level for NSCLC of ≥10% 3+ results in an ORR of 35%, 40%, 45% or higher. In embodiments, the treatment of a population of selected subjects having EGFR-mu NSQ NSCLC tumors that exhibit a positive c-Met expression level for NSCLC of ≥10% 3+ is with a regimen that results in an ORR of 35%, 40%, 45% or higher when subjects that 1) meet the eligibility criteria of section 8.2.1 and 2) have EGFR- mu NSQ NSCLC tumors that exhibit a positive c-Met expression level for NSCLC of ≥10% 3+ are treated. In embodiments, treatment of selected subjects having EGFR-mu NSQ NSCLC tumors that exhibit a positive c-Met expression level for NSCLC of ≥50% 3+ results in an ORR of 35%, 40%, 45% or higher. In embodiments, the treatment of a population of selected subjects 53 158929154.2having EGFR-mu NSQ NSCLC tumors that exhibit a positive c-Met expression level for NSCLC of ≥50% 3+ is with a regimen that results in an ORR of 35%, 40%, 45% or higher when subjects that 1) meet the eligibility criteria of section 8.2.1 and 2) have EGFR-mu NSQ NSCLC tumors that exhibit a positive c-Met expression level for NSCLC of ≥50% 3+ are treated.

[0157] In embodiments, subjects with tumors not meeting the criteria set forth in this section, (e.g., including but not limited to refractory or relapsed) are excluded from treatment. 7.3.2 Gastroesophageal Adenocarcinoma (“GEA”)

[0158] In another aspect, provided herein is a method of treating a gastroesophageal adenocarcinoma (“GEA”) tumor, comprising administering to a human subject or population of human subjects having said GEA tumor a therapeutically effective amount of ADC1, wherein ADC1 has the following structure:

[0159] wherein n is 2, 4, 6, 8, or 10, and wherein Ab is telisotuzumab, thereby treating said GEA tumor.

[0160] In a preferred embodiment, ADC1 is administered to the human patient once every three (3) weeks at a dose of 1.6 mg / kg, 2.4 mg / kg, 3.0 mg / kg, 3.5 mg / kg, 4.0 mg / kg, or 6.0 mg / kg. In a preferred embodiment, ADC1 is administered parenterally. In a preferred embodiment, the parenteral administration is intravenous administration. In a preferred embodiment, ADC1 is administered once every three weeks until disease progression, withdrawal of consent, or unacceptable toxicity.

[0161] In certain embodiments, the GEA tumor is at an advanced stage. In certain embodiments, the GEA tumor is a relapsed GEA tumor. In certain embodiments, the GEA tumor is a refractory or relapsed GEA tumor. 54 158929154.2

[0162] In certain embodiments, the GEA tumor has progressed on an immune checkpoint inhibitor.

[0163] In specific embodiments, the GEA tumor has progressed on appropriate available therapy(ies) (including HER2-directed therapy(ies)).

[0164] In specific embodiments, the GEA tumor is an advanced solid tumor that has progressed on all standard of care therapy(ies) and is not amenable to surgical resection or other approved therapeutic option(s) that have demonstrated clinical benefit.

[0165] In various embodiments, the GEA tumor expresses c-Met. In embodiments, only subjects with a GEA tumor that expresses c-Met are treated, and subjects with other GEA tumors, e.g., tumors without c-Met expression are excluded from treatment. In specific embodiments, the GEA tumor is advanced histopathologically or cytologically confirmed GEA that has progressed after treatment with at least 1 prior cytotoxic chemotherapeutic regimen for locally advanced or metastatic disease and is not amenable to surgical resection, and the human subject has not received more than 2 prior lines of cytotoxic chemotherapy regimens. In specific embodiments, the GEA tumor has progressed on an immune checkpoint inhibitor. In specific embodiments, the GEA tumor has progressed on appropriate available therapy(ies) (including HER2-directed therapy(ies)).

[0166] In various embodiments, subjects having a GEA tumor are treated without knowledge or assessment of GEA tumor c-Met expression.

[0167] In one embodiment, the method of treatment comprises the steps of determining the level of c-Met expression within the GEA tumor by performing c-Met immunohistochemistry (IHC) on tumor tissue (i.e., obtained from a biopsy, resection or cytology sample; the tumor tissue can be archival tumor tissue or fresh tumor tissue) from the subject. In embodiments, subjects having a “positive c-Met expression level for GEA” are treated, with positive c-Met expression level for GEA defined by ≥90% of neoplastic cells from tumor tissue assessed by c-Met IHC having at least 1+ membrane or membrane + cytoplasm staining (≥90% 1+). In embodiments, subjects having a “positive c-Met expression level for GEA” are treated, with positive c-Met expression level for GEA defined by ≥50% of neoplastic cells from tumor tissue assessed by c-Met IHC having at least 2+ membrane or membrane + cytoplasm staining (≥50% 2+). In embodiments, subjects having a “positive c-Met expression level for GEA” are treated, with positive c-Met expression level for GEA defined by ≥50% of neoplastic cells from tumor tissue assessed by c-Met IHC having at least 2+ membrane or 55 158929154.2membrane + cytoplasm staining. In embodiments, subjects having a “positive c-Met expression level for GEA” are treated, with positive c-Met expression level for GEA defined by ≥75% of neoplastic cells from tumor tissue assessed by c-Met IHC having at least 2+ membrane or membrane + cytoplasm staining. In embodiments, subjects having a “positive c-Met expression level for GEA” are treated, with positive c-Met expression level for GEA defined by ≥10% of neoplastic cells from tumor tissue assessed by c-Met IHC having at least 3+ membrane or membrane + cytoplasm staining. In embodiments, subjects having a “positive c-Met expression level for GEA” are treated, with positive c-Met expression level for GEA defined by ≥25 of neoplastic cells from tumor tissue assessed by c-Met IHC having at least 3+ membrane or membrane + cytoplasm staining. In embodiments, subjects having a “positive c-Met expression level for GEA” are treated, with positive c-Met expression level for GEA defined by ≥50% of neoplastic cells from tumor tissue assessed by c-Met IHC having at least 3+ membrane or membrane + cytoplasm staining.

[0168] In embodiments, only those subjects having a positive c-Met expression level for GEA are treated. In embodiments, subjects who do not exhibit positive c-Met expression level for GEA are excluded from treatment. In embodiments, a population of subjects having GEA tumors are evaluated for GEA tumor c-Met expression and those exhibiting positive c- Met expression level for GEA are selected for treatment, and those not exhibiting positive c- Met expression level for GEA are excluded from treatment.

[0169] The level of c-Met expression of the GEA tumor is taken to be that of its sampled tissue, as determined by c-Met IHC. In some embodiments, the c-Met IHC is performed according to the c-Met Staining Protocol.

[0170] In embodiments, treatment of selected subjects having GEA tumors that exhibit a positive c-Met expression level for GEA of ≥90% 1+ results in an ORR of 30%, 35% or higher.

[0171] In embodiments, treatment of selected subjects having GEA tumors that exhibit a positive c-Met expression level for GEA of ≥50% 2+ results in an ORR of 30%, 35%, 37% or higher.

[0172] In embodiments, treatment of selected subjects having GEA tumors that exhibit a positive c-Met expression level for GEA of ≥75% 2+ results in an ORR of 35%, 40%, 45% or higher. 56 158929154.2

[0173] In embodiments, treatment of selected subjects having GEA tumors that exhibit a positive c-Met expression level for GEA of ≥10% 3+ results in an ORR of 45%, 50%, 55% or higher.

[0174] In embodiments, treatment of selected subjects having GEA tumors that exhibit a positive c-Met expression level for GEA of ≥25% 3+ results in an ORR of 45%, 50%, 55%, 58% or higher.

[0175] In embodiments, patients with GEA tumors are treated with the anti-c-Met ADC in combination with a therapeutically effective dosing regimen of an anti-PD1 or anti-PD-L1 antibody. In embodiments, the anti-c-Met ADC is administered in combination with an anti- PD1 antibody, wherein the anti-PD1 antibody is budigalimab, nivolumab, pembrolizumab, cemiplimab, dostarlimab, retifanlimab or toripalimab. In embodiments, the anti-c-Met ADC is administered in combination with an anti-PD-L1 antibody, wherein the anti-PD-L1 antibody is atezolizumab, avelumab, durvalumab.

[0176] In embodiments, the anti-c-Met ADC is administered in combination with an anti- PD1 or anti-PD-L1 antibody, fluorouracil (5-FU) and leucovorin (LV) / folinic acid. In an embodiment, the anti-c-Met ADC is administered in combination with an anti-PD1 or anti- PD-L1 antibody, fluorouracil (5-FU) and leucovorin (LV) / folinic acid, wherein the anti-c- Met ADC is administered at a dose of 2.4 or 3.0 mg / kg once every four weeks, 5-FU is administered at a dose of 2400 mg / m2once every two weeks and leucovorin is administered at a dose of 400 mg / m2once every two weeks.. In an embodiment, the anti-c-Met ADC is administered in combination with an anti-PD1 or anti-PD-L1 antibody, fluorouracil (5-FU) and leucovorin (LV) / folinic acid, wherein the anti-c-Met ADC is administered at a dose of 2.4 or 3.0 mg / kg once every three weeks, 5-FU is administered at a dose of 2400 mg / m2once every two weeks and leucovorin is administered at a dose of 400 mg / m2once every two weeks. In an embodiment, the anti-c-Met ADC is administered in combination with an anti- PD1 or anti-PD-L1 antibody, fluorouracil (5-FU) and leucovorin (LV) / folinic acid, wherein the anti-c-Met ADC is administered at a dose of 1.2, 1.6 or 2.0 mg / kg once every two weeks, 5-FU is administered at a dose of 2400 mg / m2once every two weeks and leucovorin administered at a dose of 400 mg / m2once every two weeks.

[0177] In embodiments, the anti-c-Met ADC is administered in combination with fluorouracil (5-FU), leucovorin (LV) / folinic acid, and budigalimab. In embodiments, the anti- c-Met ADC is administered at a dose of 2.4 or 3.0 mg / kg once every four weeks, budigalimab 57 158929154.2is administered at a dose of 500 mg once every four weeks, 5-FU is administered at a dose of 2400 mg / m2once every two weeks and leucovorin is administered at a dose of 400 mg / m2once every two weeks. In embodiments, the c-Met-ADC and budigalimab are administered on the same day once every four weeks. In embodiments, the anti-c-Met ADC is administered at a dose of 1.2 or 2.4 mg / kg once every two weeks, budigalimab is administered at a dose of 250 mg once every two weeks, 5-FU is administered at a dose of 2400 mg / m2once every two weeks and leucovorin administered at a dose of 400 mg / m2once every two weeks. In embodiments, the c-Met-ADC and budigalimab are administered on the same day once every two weeks. In embodiments, the anti-c-Met ADC is administered once every four weeks, budigalimab is administered once every two weeks, and the anti-c-Met ADC is administered on the same day as every other budigalimab administration.

[0178] In embodiments, the anti-c-Met ADC is administered in combination with ramucirumab. In embodiments, treatment of subjects with the combination of the anti-c-Met and ramucirumab is limited to those who previously received a prior line of systemic therapy for advanced or metastatic disease that included a fluoropyrimidine and a platinum agent and have experienced documented, objective radiographic or clinical disease progression on or following completion of that systemic therapy. In embodiments, the anti-c-Met ADC is administered at a dose of 1.2, 1.6, 2.4 or 3.0 mg / kg once every three weeks and ramucirumab is administered at a therapeutically effective dosing regimen. In embodiments, the anti-c-Met ADC is administered at a dose of 1.6 mg / kg once every three weeks and ramucirumab is administered at a therapeutically effective dosing regimen. In embodiments, the anti-c-Met ADC is administered at a dose of 2.4 mg / kg once every three weeks and ramucirumab is administered at a therapeutically effective dosing regimen.

[0179] In specific embodiments, the GEA tumor is a refractory or relapsed GEA tumor, a therapeutically effective amount of 2.4 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to the human subject, the anti-c-Met ADC has an average DAR of about 6, and administration of the anti-c-Met ADC achieves PR in the human subject. In specific embodiments, the GEA tumor is a refractory or relapsed GEA tumor, a therapeutically effective amount of 3.0 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to the human subject, the anti-c-Met ADC has an average DAR of about 6, and administration of the anti-c-Met ADC achieves PR in the human subject. In specific embodiments, the GEA tumor is a refractory or relapsed GEA tumor, a therapeutically effective amount of 2.4 mg / kg of the anti-c-Met ADC is administered 58 158929154.2intravenously every three weeks to a plurality of human subjects, the anti-c-Met ADC has an average DAR of about 6, and administration of the anti-c-Met ADC provides an overall response rate that is at least 25%. In specific embodiments, the GEA tumor is a refractory or relapsed GEA tumor, a therapeutically effective amount of 3.0 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to a plurality of human subjects, the anti-c- Met ADC has an average DAR of about 6, and administration of the anti-c-Met ADC provides an overall response rate that is at least 25%.

[0180] In embodiments, subjects having GEA treated according to the methods of this section experience an overall response rate (“ORR”) of 20% or higher, for example 25%, 30% or higher. In embodiments, the treatment of a population of selected subjects having GEA tumors is with a regimen that results in an ORR of 20% or higher, for example 25%, 30% or higher when subjects that 1) meet the eligibility criteria of section 8.2.1 and 2) have GEA tumors are treated.

[0181] In embodiments, subjects having GEA treated according to the methods of this section experience a clinical benefit rate (“CBR”) of 60% or higher, for example 70% or 80% or higher. In embodiments, the treatment of a population of selected subjects having GEA tumors is with a regimen that results in a CBR of 60% or higher, for example 70% or 80% or higher when subjects that 1) meet the eligibility criteria of section 8.2.1 and 2) have GEA tumors are treated.

[0182] In an embodiment, the confirmed clinical benefit rate at 12 weeks (CBR12) is 30%, 35% 40% or higher. In embodiments, the treatment of a population of selected subjects having GEA tumors is with a regimen that results in a CBR12 of 30%, 35% 40% or higher when subjects that 1) meet the eligibility criteria of section 8.2.1 and 2) have GEA tumors are treated.

[0183] In one embodiment, the method of treatment comprises the steps of determining the level of MET gene amplification within the GEA tumor. Detection of MET gene amplification can be carried out, for example, by fluorescence in situ hybridization (FISH). In embodiments, the MET amplification is a focal MET gene amplification, which is an amplification of a portion of a chromosome and is distinguished from amplification due to aneuploidy. In embodiments, the detection is preformed according to the MET FISH protocol described in section 7.4 and Example 5 herein. 59 158929154.2

[0184] In embodiments, subjects positive for MET gene amplification are treated. In embodiments, only those subjects positive for MET gene amplification are treated. In embodiments, subjects who do not exhibit positive MET gene amplification are excluded from treatment. In embodiments, a population of subjects having GEA tumors are evaluated for GEA tumor MET gene amplification and those positive for MET gene amplification are selected for treatment, and those not exhibiting MET gene amplification are excluded from treatment.

[0185] In embodiments, treatment of selected subjects having GEA tumors that exhibit positive MET gene amplification results in an ORR of 50%, 55%, 60% or higher. In embodiments, the treatment of a population of selected subjects having GEA tumors that exhibit positive MET gene amplification is with a regimen that results in an ORR of 50%, 55%, 60% or higher when subjects that 1) meet the eligibility criteria of section 8.2.1 and 2) have GEA tumors that exhibit positive MET gene amplification are treated.

[0186] In embodiments, treatment of selected subjects having GEA tumors that exhibit positive focal MET gene amplification results in an ORR of 60%, 65%, 70%, 75%, 80% or higher. In embodiments, the treatment of a population of selected subjects having GEA tumors that exhibit positive focal MET gene amplification is with a regimen that results in an ORR of 60%, 65%, 70%, 75%, 80% or higher when subjects that 1) meet the eligibility criteria of section 8.2.1 and 2) have GEA tumors that exhibit positive focal MET gene amplification are treated.

[0187] In embodiments, MET gene amplification is detected by determination of gene copy number. Gene copy number can be determined by, for example, next generation sequencing (NGS), or PCR techniques as means for determining c-Met-gene amplification in the GEA tumor of a candidate patient for treatment with the anti-c-Met ADC. These techniques can be performed on tumor tissue or a blood sample from the patient.

[0188] In embodiments, subjects with tumors not meeting the criteria set forth in this section, (e.g., including but not limited to refractory or relapsed) are excluded from treatment. 7.3.3 Colorectal Cancer (“CRC”)

[0189] In another aspect, provided herein is a method of treating a colorectal cancer (“CRC”) tumor, comprising administering to a human subject or population of human subjects having said CRC tumor a therapeutically effective amount of ADC1, wherein ADC1 has the following structure: 60 158929154.2

[0190] wherein n is 2, 4, 6, 8, or 10, and wherein Ab is telisotuzumab, thereby treating said CRC tumor.

[0191] In a preferred embodiment, ADC1 is administered to the human patient once every three (3) weeks at a dose of 1.6 mg / kg, 2.4 mg / kg, 3.0 mg / kg, 3.5 mg / kg, 4.0 mg / kg, or 6.0 mg / kg. In a preferred embodiment, ADC1 is administered parenterally. In a preferred embodiment, the parenteral administration is intravenous administration. In a preferred embodiment, ADC1 is administered once every three weeks until disease progression, withdrawal of consent, or unacceptable toxicity.

[0192] In an embodiment, ADC1 is administered for the treatment of CRC in a human patient in combination with bevacizumab. In embodiments, bevacizumab is administered Q3W at a dose of 7.5 mg / kg. In embodiments, ADC1, when administered in the aforementioned combination with bevacizumab, is administered to the human patient once every three (3) weeks at a dose of 1.6 mg / kg, 2.4 mg / kg, or 3.0 mg / kg. For subjects receiving the combination of ADC1 and bevacizumab, in embodiments such subjects are those with history of advanced histopathologically or cytologically confirmed CRC that does not harbor the BRAF V600E mutation, does not have defective DNA mismatch repair (dMMR), and is not microsatellite instability-high (MSI-H), with progression on a fluoropyrimidine (e.g., 5- fluorouracil or capecitabine), oxaliplatin, irinotecan. In embodiments, subjects receiving the combination of ADC1 and bevacizumab were not treated previously with TAS-102 or regorafenib.

[0193] In an embodiment, ADC1 is administered for the treatment of CRC in a human patient in combination with fluorouracil, folinic acid and bevacizumab. In embodiments, the patients receiving the combination of ADC1, fluorouracil, folinic acid and bevacizumab are those with unresectable mCRC who are MSS or pMMr, BRAF V600E wild-type, and have progressed after first line treatment of combination chemotherapy with or without an anti- 61 158929154.2VEGF or an anti-EGFR antibody. In embodiments, fluorouracil is administered Q2W at a dose of 2400 g / m2, folinic acid is administered Q2W at dose of 200 mg / m2, and bevacizumab is administered Q2W at a dose of 5 mg / kg. In embodiments, ADC1, when administered in the aforementioned combination with fluorouracil, folinic acid and bevacizumab, is administered to the human patient at a dosage and frequency of 1) once every three (3) weeks at a dose of 1.6 mg / kg, 2.4 mg / kg, 3.0 mg / kg, 3.5 mg / kg, 4.0 mg / kg, or 6.0 mg / kg; 2) once every 2 weeks at dose of 0.8 mg / kg, 1.0 mg / kg, 1.2 mg / kg, 1.6 mg / kg, 2.0 mg / kg, or 2.4 mg / kg; or 3) once every 4 weeks at dose of 1.6 mg / kg, 2.0 mg / kg, 2.4 mg / kg, or 3.0 mg / kg.

[0194] In a preferred embodiment, ADC1 is administered parenterally. In a preferred embodiment, the parenteral administration is intravenous administration. In a preferred embodiment, ADC1 is administered once every three weeks until disease progression, withdrawal of consent, or unacceptable toxicity.

[0195] In certain embodiments, the CRC tumor is at an advanced stage. In certain embodiments, the CRC tumor is a relapsed CRC tumor. In certain embodiments, the CRC tumor is a refractory or relapsed CRC tumor.

[0196] In certain embodiments, the CRC tumor has progressed on any one or a combination of prior treatments including a fluoropyrimidine (e.g., 5-fluorouracil or capecitabine), oxaliplatin, irinotecan, an anti-EGFR antibody (e.g., cetuximab or panitumumab), and / or an anti-vascular endothelial growth factor (VEGF) monoclonal antibody (e.g., bevacizumab, ramucirumab, or aflibercept).

[0197] In certain embodiments, the CRC tumor has progressed on an applicable targeted therapy.

[0198] In certain embodiments, the human subject is considered ineligible for or is intolerant of standard therapy per the treating physician.

[0199] In certain embodiments, the CRC tumor is an advanced solid tumor that has progressed on all standard of care therapy(ies) and is not amenable to surgical resection or other approved therapeutic option(s) that have demonstrated clinical benefit.

[0200] In certain embodiments, the CRC tumor does not harbor the BRAF V600E mutation. In certain embodiments, the CRC tumor is not dMMR+ / MSI-Hi. In certain embodiments, the CRC tumor does not harbor the BRAF V600E mutation and is not dMMR+ / MSI-Hi. In embodiments, only subjects with a CRC tumor that is not dMMR+ / MSI-Hi are treated, and subjects with CRC tumors that are dMMR+ / MSI-Hi are excluded from treatment. In 62 158929154.2embodiments, only subjects with a CRC tumor that does not harbor the BRAF V600E mutation are treated, and subjects with CRC tumors that harbor the BRAF V600E mutation are excluded from treatment. In specific embodiments, the CRC tumor is advanced histopathologically or cytologically confirmed CRC that does not harbor the BRAF V600E mutation and is not dMMR+ / MSI-Hi. In specific embodiments, the CRC tumor has progressed on any one or a combination of prior treatments including a fluoropyrimidine (e.g., 5-fluorouracil or capecitabine), oxaliplatin, irinotecan, an anti-EGFR antibody (e.g., cetuximab or panitumumab), and / or an anti-vascular endothelial growth factor (VEGF) monoclonal antibody (e.g., bevacizumab, ramucirumab, or aflibercept). In specific embodiments, the CRC tumor has progressed on an applicable targeted therapy.

[0201] In various embodiments, the CRC tumor expresses c-Met. In embodiments, only subjects with a CRC tumor that expresses c-Met are treated, and subjects with tumors that do not express c-Met are excluded from treatment. In certain embodiments, the c-Met expressing CRC tumor is a histologically or cytologically confirmed locally advanced or metastatic tumor with progression following at least 1 prior line of systemic therapy administered in the advanced / metastatic setting.

[0202] In various embodiments, subjects having a CRC tumor are treated without knowledge or assessment of CRC tumor c-Met expression.

[0203] In specific embodiments, the CRC tumor is a refractory or relapsed CRC tumor, a therapeutically effective amount of 2.4 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to the human subject, the anti-c-Met ADC has an average DAR of about 6, and administration of the anti-c-Met ADC achieves PR in the human subject. In specific embodiments, the CRC tumor is a refractory or relapsed CRC tumor, a therapeutically effective amount of 3.0 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to the human subject, the anti-c-Met ADC has an average DAR of about 6, and administration of the anti-c-Met ADC achieves PR in the human subject.

[0204] In specific embodiments, the CRC tumor is a refractory or relapsed CRC tumor, a therapeutically effective amount of 2.4 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to a plurality of human subjects, the anti-c-Met ADC has an average DAR of about 6, and administration of the anti-c-Met ADC provides an overall response rate that is greater than 25%. In specific embodiments, the CRC tumor is a 63 158929154.2refractory or relapsed CRC tumor, a therapeutically effective amount of 3.0 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to a plurality of human subjects, the anti-c-Met ADC has an average DAR of about 6, and administration of the anti- c-Met ADC provides an overall response rate that is greater than 15%.

[0205] In specific embodiments, the subject having the CRC tumor has not received first- line systemic treatment for CRC (including combination chemotherapy with or without targeted therapy), optionally prior adjuvant chemotherapy for localized CRC is allowed given that treatment was completed ≥ 12 months prior to treatment with the anti-c-Met ADC; has not received any prior systemic regimen containing c-Met targeting antibody or ADC; and has no evidence of active interstitial lung disease or pneumonitis by screening chest CT scan. In embodiments, the subject meets one or more of the above criteria. In embodiments, the subject of this paragraph is treated with the c-Met ADC in combination with chemotherapy and / or other antibodies. In embodiments, the c-Met ADC is administered in combination with leucovorin (LV), fluorouracil (5-FU) or oxaliplatin (FOLFOX). In embodiments, c-Met ADC is administered in combination with 5-FU / LV. In embodiments, c-Met ADC is administered in combination with 5-FU / LV and panatimumab. In embodiments, the c-Met ADC is administered in combination with 5-FU / LV and bevacizumab. In embodiments, the c-Met ADC is administered in combination with FOLFOX and bevacizumab.

[0206] In specific embodiments, the subject is one 1) with a CRC tumor that is a left sided primary tumor; 2) whose tumor has been classified as KRAS / NRAS / BRAFV600E wild-type; 3) whose tumor is not dMMR+ / MSI-H; 4) who has not received first line systemic treatment for CRC (including combination chemotherapy with or without targeted therapy), optionally with prior adjuvant chemotherapy for localized CRC given that treatment was completed ≥ 12 months prior to treatment the anti-c-Met ADC; 5) who has not received prior treatment with any anti-EGFR drugs; 6) who has not received prior systemic regimen containing c-Met targeting antibody or ADC; 7) who has no evidence of active interstitial lung disease or pneumonitis on screening chest CT scan. In embodiments, the subject meets one or more of the above criteria. In embodiments, the subject of this paragraph is treated with the c-Met ADC in combination with chemotherapy.

[0207] In embodiments, subjects having CRC treated according to the methods of this section experience an overall response rate (“ORR”) of 15% or higher, for example 20%, 22%, 24%, 25%, 30%, or 35% or higher. In embodiments, the treatment of a population of selected subjects having CRC tumors is with a regimen that results in an ORR of 15% or 64 158929154.2higher, for example 20%, 22%, 24%, 25%, 30%, or 35% or higher when subjects that 1) meet the eligibility criteria of section 8.2.1 and 2) have CRC tumors are treated.

[0208] In embodiments, subjects having CRC treated according to the methods of this section experience a clinical benefit rate (“CBR”) of 60% or higher, for example 70% or 80% or higher. In embodiments, the treatment of a population of selected subjects having CRC tumors is with a regimen that results in an CBR of 60% or higher, for example 70%, 80% or higher when subjects that 1) meet the eligibility criteria of section 8.2.1 and 2) have CRC tumors are treated.

[0209] In embodiments, subjects having CRC treated according to the methods of this section experience a clinical benefit rate at 12 weeks (“CBR12”) of 40% or higher, for example 50% or 60% or higher. In embodiments, the treatment of a population of selected subjects having CRC tumors is with a regimen that results in an CBR12 of 40% or higher, for example 50%, 60% or higher when subjects that 1) meet the eligibility criteria of section 8.2.1 and 2) have CRC tumors are treated.

[0210] In embodiments, subjects having CRC treated according to the methods of this section experience a clinical benefit rate at 24 weeks (“CBR24”) of 30% or higher, for example 40% or 50% or higher. In embodiments, the treatment of a population of selected subjects having CRC tumors is with a regimen that results in an CBR24 of 30% or higher, for example 40%, 50% or higher when subjects that 1) meet the eligibility criteria of section 8.2.1 and 2) have CRC tumors are treated.

[0211] In embodiments, subjects having CRC treated according to the methods of this section experience progression free survival (“PFS”) of 3 months or greater than 3 months, 4 months or greater than 4 months, 5 months or greater than 5 months or 6 months or greater than 6 months. In embodiments, the treatment of a population of selected subjects having CRC tumors is with a regimen that results in PFS of 3 months or greater than 3 months, 4 months or greater than 4 months, 5 months or greater than 5 months or 6 months or greater than 6 months when subjects that 1) meet the eligibility criteria of section 8.2.1 and 2) have CRC tumors are treated.

[0212] In embodiments, subjects having CRC treated according to the methods of this section experience duration of response (“DoR”) of 3 months or greater than 3 months, 4 months or greater than 4 months, 5 months or greater than 5 months or 6 months or greater than 6 months. In embodiments, the treatment of a population of selected subjects having 65 158929154.2CRC tumors is with a regimen that results in a DOR of 3 months or greater than 3 months, 4 months or greater than 4 months, 5 months or greater than 5 months or 6 months or greater than 6 months when subjects that 1) meet the eligibility criteria of section 8.2.1 and 2) have CRC tumors are treated.

[0213] In one embodiment, the method of treatment comprises the steps of determining the level of c-Met expression within the CRC tumor by performing c-Met immunohistochemistry (IHC) on tumor tissue (i.e., obtained from a biopsy, resection or cytology sample; the tumor tissue can be archival tumor tissue or fresh tumor tissue) from the subject. In embodiments, subjects having a “positive c-Met expression level for CRC” are treated, with positive c-Met expression level for CRC defined by ≥10% of neoplastic cells from tumor tissue assessed by c-Met IHC having 3+ membrane or membrane + cytoplasm staining. In embodiments, positive c-Met expression level for CRC is defined by ≥50% of neoplastic cells from tumor tissue assessed by c-Met IHC having 2+ membrane or membrane + cytoplasm staining. In embodiments, positive c-Met expression level for CRC is defined by ≥75% of neoplastic cells from tumor tissue assessed by c-Met IHC having 2+ membrane or membrane + cytoplasm staining.

[0214] In embodiments, only those subjects having a positive c-Met expression level for CRC are treated. In embodiments, subjects who do not exhibit positive c-Met expression level for CRC are excluded from treatment. In embodiments, a population of subjects having CRC tumors are evaluated for CRC tumor c-Met expression and those exhibiting positive c- Met expression level for CRC are selected for treatment, and those not exhibiting positive c- Met expression level for CRC are excluded from treatment. In embodiments, subjects having positive c-Met expression levels for CRC are treated with administration of the c-Met ADC in combination with chemotherapy and / or other antibodies, for example, c-Met ADC in combination with 5-FU / LV; FOLFOX; 5-FU / LV and panatimumab; 5-FU / LV and bevacizumab; or FOLFOX and bevacizumab.

[0215] In embodiments, treatment of selected subjects having CRC tumors that exhibit a positive c-Met expression level for CRC results in an ORR of 30%, 35%, 37% or higher. In embodiments, the treatment of a population of selected subjects having CRC tumors that exhibit a positive c-Met expression level for CRC is with a regimen that results in an ORR of 30%, 35%, 37% or higher when subjects that 1) meet the eligibility criteria of section 8.2.1 and 2) have CRC tumors that exhibit a positive c-Met expression level for CRC are treated. 66 158929154.2

[0216] In embodiments, treatment of selected subjects having CRC tumors that exhibit a positive c-Met expression level for CRC results in a median PFS of 5, 5.2, 5.4, 5.5 months or longer. In embodiments, the treatment of a population of selected subjects having CRC tumors that exhibit a positive c-Met expression level for CRC is with a regimen that results in a median PFS of 5, 5.2, 5.4, 5.5 months or longer when subjects that 1) meet the eligibility criteria of section 8.2.1 and 2) have CRC tumors that exhibit a positive c-Met expression level for CRC are treated.

[0217] The level of c-Met expression of the CRC tumor is taken to be that of its sampled tissue, as determined by c-Met IHC. In some embodiments, the c-Met IHC is performed according to the c-Met Staining Protocol.

[0218] In embodiments, subjects with tumors not meeting the criteria set forth in this section, (e.g., including but not limited to refractory or relapsed) are excluded from treatment. 7.3.4 MET Gene Amplified Advanced Solid Tumor

[0219] In another aspect, provided herein is a method of treating a MET gene amplified advanced solid tumor, comprising administering to a human subject or population of human subjects having said MET gene amplified advanced solid tumor a therapeutically effective amount of ADC1, wherein ADC1 has the following structure:

[0220] wherein n is 2, 4, 6, 8, or 10, and wherein Ab is telisotuzumab, thereby treating said MET gene amplified advanced solid tumor.

[0221] In a preferred embodiment, ADC1 is administered to the human patient once every three (3) weeks at a dose of 1.6 mg / kg, 2.4 mg / kg, 3.0 mg / kg, 3.5 mg / kg, 4.0 mg / kg, or 6.0 mg / kg. In a preferred embodiment, ADC1 is administered parenterally. In a preferred embodiment, the parenteral administration is intravenous administration. In a preferred 67 158929154.2embodiment, ADC1 is administered once every three weeks until disease progression, withdrawal of consent, or unacceptable toxicity.

[0222] In embodiments, only subjects with a MET gene amplified advanced solid tumor are treated, and subjects with solid tumors that are not MET gene amplified are excluded from treatment. In certain embodiments, the MET gene amplified advanced solid tumor is a relapsed MET gene amplified advanced solid tumor. In certain embodiments, the MET gene amplified advanced solid tumor is a refractory or relapsed MET gene amplified advanced solid tumor.

[0223] In various embodiments, the MET gene amplified advanced solid tumor expresses c- Met. In embodiments, only subjects with a MET gene amplified advanced solid tumor that expresses c-Met are treated, and subjects with tumors that do not express c-Met are excluded from treatment.

[0224] In various embodiments, subjects having a MET gene amplified advanced solid tumor are treated without knowledge or assessment of MET gene amplified advanced solid tumor c- Met expression.

[0225] In specific embodiments, the MET gene amplified advanced solid tumor is a refractory or relapsed MET gene amplified advanced solid tumor, a therapeutically effective amount of 2.4 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to the human subject, the anti-c-Met ADC has an average DAR of about 6, and administration of the anti-c-Met ADC achieves PR in the human subject.

[0226] In specific embodiments, the MET gene amplified advanced solid tumor is a refractory or relapsed MET gene amplified advanced solid tumor, a therapeutically effective amount of 3.0 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to the human subject, the anti-c-Met ADC has an average DAR of about 6, and administration of the anti-c-Met ADC achieves PR in the human subject.

[0227] In specific embodiments, the MET gene amplified advanced solid tumor is a refractory or relapsed MET gene amplified advanced solid tumor, a therapeutically effective amount of 2.4 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to a plurality of human subjects, the anti-c-Met ADC has an average DAR of about 6, and administration of the anti-c-Met ADC provides an overall response rate that is greater than 25%. In specific embodiments, the MET gene amplified advanced solid tumor is a refractory or relapsed MET gene amplified advanced solid tumor, a therapeutically effective amount of 68 158929154.23.0 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to a plurality of human subjects, the anti-c-Met ADC has an average DAR of about 6, and administration of the anti-c-Met ADC provides an overall response rate that is greater than 25%.

[0228] In some embodiments, MET gene amplification is determined using a next generation sequencing assay (NGS). In some embodiments, MET gene amplification is determined using a fluorescence in situ hybridization assay (FISH). In a preferred embodiment, FISH is carried out on formalin-fixed paraffin-embedded (FFPE) tissue, an unstained sliced histological sample undergoes a standard procedure of deparaffinization and rehydration followed by digestion using a protease solution, next, cellular DNA of the sample and the probes are denatured followed by hybridization of the probes with the target DNA sequence, and FISH results are obtained by counting hybridization signals of the probes in each cell.

[0229] In embodiments, subjects having MET amplified tumors treated according to the methods of this section experience an overall response rate (“ORR”) of 30% or higher, for example 40%, 50%, 60% or 70% or higher. In embodiments, subjects MET amplified tumors treated according to the methods of this section experience a clinical benefit rate (“CBR”) of 60% or higher, for example 70% or 80% or higher.

[0230] In embodiments, subjects with tumors not meeting the criteria set forth in this section, (e.g., including but not limited to locally advanced, and refractory or relapsed) are excluded from treatment. 7.3.5 Hepatocellular Carcinoma (“HCC”)

[0231] In another aspect, provided herein is a method of treating a hepatocellular carcinoma (“HCC”) tumor, comprising administering to a human subject or population of human subjects having said HCC tumor a therapeutically effective amount of ADC1, wherein ADC1 has the following structure: 69 158929154.2

[0232] wherein n is 2, 4, 6, 8, or 10, and wherein Ab is telisotuzumab, thereby treating said HCC tumor.

[0233] In a preferred embodiment, ADC1 is administered to the human patient once every three (3) weeks at a dose of 1.6 mg / kg, 2.4 mg / kg, 3.0 mg / kg, 3.5 mg / kg, 4.0 mg / kg, or 6.0 mg / kg. In a preferred embodiment, ADC1 is administered parenterally. In a preferred embodiment, the parenteral administration is intravenous administration. In a preferred embodiment, ADC1 is administered once every three weeks until disease progression, withdrawal of consent, or unacceptable toxicity.

[0234] In certain embodiments, the HCC tumor is at an advanced stage. In certain embodiments, the HCC tumor is a relapsed HCC tumor. In certain embodiments, the HCC tumor is a refractory or relapsed HCC tumor. In certain embodiments, the HCC tumor is locally advanced or metastatic HCC with disease progression during or after 1 prior line of systemic therapy.

[0235] In various embodiments, the HCC tumor expresses c-Met. In embodiments, only subjects with an HCC tumor that expresses c-Met are treated, and subjects with solid tumors that do not express c-Met are excluded from treatment. In certain embodiments, the c-Met expressing HCC tumor is at an advanced stage. In certain embodiments, the c-Met expressing HCC tumor is a relapsed HCC tumor. In certain embodiments, the c-Met expressing tumor is a refractory or relapsed HCC tumor. In certain embodiments, the c-Met expressing tumor is locally advanced or metastatic HCC with disease progression during or after 1 prior line of systemic therapy.

[0236] In various embodiments, subjects having an HCC tumor are treated without knowledge or assessment of HCC tumor c-Met expression. 70 158929154.2

[0237] In specific embodiments, the HCC tumor is a locally advanced or metastatic HCC tumor with disease progression during or after 1 prior line of systemic therapy, a therapeutically effective amount of 2.4 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to the human subject, the anti-c-Met ADC has an average DAR of about 6, and administration of the anti-c-Met ADC achieves PR in the human subject. In specific embodiments, the HCC tumor is a locally advanced or metastatic HCC tumor with disease progression during or after 1 prior line of systemic therapy, a therapeutically effective amount of 3.0 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to the human subject, the anti-c-Met ADC has an average DAR of about 6, and administration of the anti-c-Met ADC achieves PR in the human subject.

[0238] In specific embodiments, the HCC tumor is a locally advanced or metastatic HCC tumor with disease progression during or after 1 prior line of systemic therapy, a therapeutically effective amount of 2.4 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to a plurality of human subjects, the anti-c-Met ADC has an average DAR of about 6, and administration of the anti-c-Met ADC provides an overall response rate that is greater than 25%. In specific embodiments, the HCC tumor is a locally advanced or metastatic HCC tumor with disease progression during or after 1 prior line of systemic therapy, a therapeutically effective amount of 3.0 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to a plurality of human subjects, the anti-c-Met ADC has an average DAR of about 6, and administration of the anti-c-Met ADC provides an overall response rate that is greater than 25%.

[0239] In embodiments, subjects with tumors not meeting the criteria set forth in this section, (e.g., including but not limited to locally advanced, metastatic, and disease progression during or after 1 prior line of systemic therapy) are excluded from treatment. 7.3.6 Pancreatic Ductal Adenocarcinoma (“PDAC”)

[0240] In another aspect, provided herein is a method of treating a pancreatic ductal adenocarcinoma (“PDAC”) tumor, comprising administering to a human subject or population of human subjects having said PDAC tumor a therapeutically effective amount of ADC1, wherein ADC1 has the following structure: 71 158929154.2

[0241] wherein n is 2, 4, 6, 8, or 10, and wherein Ab is telisotuzumab, thereby treating said PDAC tumor.

[0242] In a preferred embodiment, ADC1 is administered to the human patient once every three (3) weeks at a dose of 1.6 mg / kg, 2.4 mg / kg, 3.0 mg / kg, 3.5 mg / kg, 4.0 mg / kg, or 6.0 mg / kg. In a preferred embodiment, ADC1 is administered parenterally. In a preferred embodiment, the parenteral administration is intravenous administration. In a preferred embodiment, ADC1 is administered once every three weeks until disease progression, withdrawal of consent, or unacceptable toxicity.

[0243] In certain embodiments, the PDAC tumor is histologically or cytologically confirmed advanced or metastatic PDAC with disease progression during or after 1 systemic therapy (including gemcitabine monotherapy or in combination with other agents, FOLFIRINOX [or another regimen including both 5-fluorouracil and oxaliplatin], capecitabine monotherapy or in combination with other agents) administered in the adjuvant, locally advanced, or metastatic setting.

[0244] In various embodiments, the PDAC tumor expresses c-Met. In embodiments, only subjects with a PDAC tumor that expresses c-Met are treated, and subjects with tumors that do not express c-Met are excluded from treatment. In certain embodiments, the c-Met expressing PDAC tumor is histologically or cytologically confirmed advanced or metastatic PDAC with disease progression during or after 1 systemic therapy (including gemcitabine monotherapy or in combination with other agents, FOLFIRINOX [or another regimen including both 5-fluorouracil and oxaliplatin], capecitabine monotherapy or in combination with other agents) administered in the adjuvant, locally advanced, or metastatic setting.

[0245] In various embodiments, subjects having a PDAC tumor are treated without knowledge or assessment of PDAC tumor c-Met expression. 72 158929154.2

[0246] In specific embodiments, the PDAC tumor is histologically or cytologically confirmed advanced or metastatic PDAC with disease progression during or after 1 systemic therapy, a therapeutically effective amount of 2.4 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to the human subject, the anti-c-Met ADC has an average DAR of about 6, and administration of the anti-c-Met ADC achieves PR in the human subject. In specific embodiments, the PDAC tumor is histologically or cytologically confirmed advanced or metastatic PDAC with disease progression during or after 1 systemic therapy, a therapeutically effective amount of 3.0 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to the human subject, the anti-c-Met ADC has an average DAR of about 6, and administration of the anti-c-Met ADC achieves PR in the human subject. In specific embodiments, the PDAC tumor is histologically or cytologically confirmed advanced or metastatic PDAC with disease progression during or after 1 systemic therapy, a therapeutically effective amount of 2.4 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to a plurality of human subjects, the anti-c-Met ADC has an average DAR of about 6, and administration of the anti-c-Met ADC provides an overall response rate that is greater than 25%. In specific embodiments, the PDAC tumor is histologically or cytologically confirmed advanced or metastatic PDAC with disease progression during or after 1 systemic therapy, a therapeutically effective amount of 3.0 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to a plurality of human subjects, the anti-c-Met ADC has an average DAR of about 6, and administration of the anti-c-Met ADC provides an overall response rate that is greater than 25%.

[0247] In embodiments, subjects with tumors not meeting the criteria set forth in this section, (e.g., including but not limited to histologically or cytologically confirmed advanced or metastatic and disease progression during or after 1 systemic therapy) are excluded from treatment. 7.3.7 Biliary Tract Cancer (“BTC”)

[0248] In another aspect, provided herein is a method of treating a biliary tract cancer (“BTC”) tumor, comprising administering to a human subject or population of human subjects having said BTC tumor a therapeutically effective amount of ADC1, wherein ADC1 has the following structure: 73 158929154.2

[0249] wherein n is 2, 4, 6, 8, or 10, and wherein Ab is telisotuzumab, thereby treating said BTC tumor.

[0250] In a preferred embodiment, ADC1 is administered to the human patient once every three (3) weeks at a dose of 1.6 mg / kg, 2.4 mg / kg, 3.0 mg / kg, 3.5 mg / kg, 4.0 mg / kg, or 6.0 mg / kg. In a preferred embodiment, ADC1 is administered parenterally. In a preferred embodiment, the parenteral administration is intravenous administration. In a preferred embodiment, ADC1 is administered once every three weeks until disease progression, withdrawal of consent, or unacceptable toxicity.

[0251] In certain embodiments, the BTC tumor is histologically or cytologically confirmed locally advanced or metastatic, unresectable intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, or gallbladder cancer with disease progression during or after 1 systemic therapy, including gemcitabine and / or platinum-based chemotherapy.

[0252] In various embodiments, the BTC tumor expresses c-Met. In embodiments, only subjects with a BTC tumor that expresses c-Met are treated, and subjects with tumors that do not express c-Met are excluded from treatment. In certain embodiments, the c-Met expressing BTC tumor is histologically or cytologically confirmed locally advanced or metastatic, unresectable intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, or gallbladder cancer with disease progression during or after 1 systemic therapy, including gemcitabine and / or platinum-based chemotherapy.

[0253] In various embodiments, subjects having a BTC tumor are treated without knowledge or assessment of BTC tumor c-Met expression.

[0254] In specific embodiments, the BTC tumor is histologically or cytologically confirmed locally advanced or metastatic, unresectable intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, or gallbladder cancer with disease progression during or after 1 74 158929154.2systemic therapy, a therapeutically effective amount of 2.4 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to the human subject, the anti-c-Met ADC has an average DAR of about 6, and administration of the anti-c-Met ADC achieves PR in the human subject. In specific embodiments, the BTC tumor is histologically or cytologically confirmed locally advanced or metastatic, unresectable intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, or gallbladder cancer with disease progression during or after 1 systemic therapy, a therapeutically effective amount of 3.0 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to the human subject, the anti-c-Met ADC has an average DAR of about 6, and administration of the anti-c-Met ADC achieves PR in the human subject. In specific embodiments, the BTC tumor is histologically or cytologically confirmed locally advanced or metastatic, unresectable intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, or gallbladder cancer with disease progression during or after 1 systemic therapy, a therapeutically effective amount of 2.4 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to a plurality of human subjects, the anti-c-Met ADC has an average DAR of about 6, and administration of the anti-c-Met ADC provides an overall response rate that is greater than 25%. In specific embodiments, the BTC tumor is histologically or cytologically confirmed locally advanced or metastatic, unresectable intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, or gallbladder cancer with disease progression during or after 1 systemic therapy, a therapeutically effective amount of 3.0 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to a plurality of human subjects, the anti-c-Met ADC has an average DAR of about 6, and administration of the anti-c-Met ADC provides an overall response rate that is greater than 25%.

[0255] In embodiments, subjects with tumors not meeting the criteria set forth in this section, (e.g., including but not limited to histologically or cytologically confirmed locally advanced or metastatic, unresectable intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, or gallbladder cancer with disease progression during or after 1 systemic therapy) are excluded from treatment. 7.3.8 Esophageal Squamous Cell Carcinoma (“ESCC”)

[0256] In another aspect, provided herein is a method of treating an esophageal squamous cell carcinoma (“ESCC”) tumor, comprising administering to a human subject or population of human subjects having said ESCC tumor a therapeutically effective amount of ADC1, wherein ADC1 has the following structure: 75 158929154.2

[0257] wherein n is 2, 4, 6, 8, or 10, and wherein Ab is telisotuzumab, thereby treating said ESCC tumor.

[0258] In a preferred embodiment, ADC1 is administered to the human patient once every three (3) weeks at a dose of 1.6 mg / kg, 2.4 mg / kg, 3.0 mg / kg, 3.5 mg / kg, 4.0 mg / kg, or 6.0 mg / kg. In a preferred embodiment, ADC1 is administered parenterally. In a preferred embodiment, the parenteral administration is intravenous administration. In a preferred embodiment, ADC1 is administered once every three weeks until disease progression, withdrawal of consent, or unacceptable toxicity.

[0259] In certain embodiments, the ESCC tumor is histologically or cytologically confirmed locally advanced or metastatic with disease progression on no more than 2 prior lines of cytotoxic chemotherapy.

[0260] In various embodiments, the ESCC tumor expresses c-Met. In embodiments, only subjects with a ESCC tumor that expresses c-Met are treated, and subjects with tumors that do not express c-Met are excluded from treatment. In certain embodiments, the c-Met expressing ESCC tumor is histologically or cytologically confirmed locally advanced or metastatic with disease progression on no more than 2 prior lines of cytotoxic chemotherapy.

[0261] In various embodiments, subjects having an ESCC tumor are treated without knowledge or assessment of ESCC tumor c-Met expression.

[0262] In specific embodiments, the ESCC tumor is histologically or cytologically confirmed locally advanced or metastatic with disease progression on no more than 2 prior lines of cytotoxic chemotherapy, a therapeutically effective amount of 2.4 mg / kg of the anti- c-Met ADC is administered intravenously every three weeks to the human subject, the anti-c- Met ADC has an average DAR of about 6, and administration of the anti-c-Met ADC achieves PR in the human subject. In specific embodiments, the ESCC tumor is 76 158929154.2histologically or cytologically confirmed locally advanced or metastatic with disease progression on no more than 2 prior lines of cytotoxic chemotherapy, a therapeutically effective amount of 3.0 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to the human subject, the anti-c-Met ADC has an average DAR of about 6, and administration of the anti-c-Met ADC achieves PR in the human subject. In specific embodiments, the ESCC tumor is histologically or cytologically confirmed locally advanced or metastatic with disease progression on no more than 2 prior lines of cytotoxic chemotherapy, a therapeutically effective amount of 2.4 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to a plurality of human subjects, the anti-c-Met ADC has an average DAR of about 6, and administration of the anti-c-Met ADC provides an overall response rate that is greater than 25%. In specific embodiments, the ESCC tumor is histologically or cytologically confirmed locally advanced or metastatic with disease progression on no more than 2 prior lines of cytotoxic chemotherapy, a therapeutically effective amount of 3.0 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to a plurality of human subjects, the anti-c-Met ADC has an average DAR of about 6, and administration of the anti-c-Met ADC provides an overall response rate that is greater than 25%.

[0263] In embodiments, subjects with tumors not meeting the criteria set forth in this section, (e.g., including but not limited to histologically or cytologically confirmed locally advanced or metastatic with disease progression on no more than 2 prior lines of cytotoxic chemotherapy) are excluded from treatment. 7.3.9 Triple-negative Breast Cancer (“TNBC”)

[0264] In another aspect, provided herein is a method of treating a triple-negative breast cancer tumor (“TNBC”) tumor, comprising administering to a human subject or population of human subjects having said TNBC tumor a therapeutically effective amount of ADC1, wherein ADC1 has the following structure: 77 158929154.2

[0265] wherein n is 2, 4, 6, 8, or 10, and wherein Ab is telisotuzumab, thereby treating said TNBC tumor.

[0266] In a preferred embodiment, ADC1 is administered to the human patient once every three (3) weeks at a dose of 1.6 mg / kg, 2.4 mg / kg, 3.0 mg / kg, 3.5 mg / kg, 4.0 mg / kg, or 6.0 mg / kg. In a preferred embodiment, ADC1 is administered parenterally. In a preferred embodiment, the parenteral administration is intravenous administration. In a preferred embodiment, ADC1 is administered once every three weeks until disease progression, withdrawal of consent, or unacceptable toxicity.

[0267] In certain embodiments, the TNBC tumor is histologically or cytologically confirmed locally advanced or metastatic, unresectable TNBC per American Society of Clinical Oncology / College of American Pathologists (ASCO / CAP) criteria with progression following at least 1 prior line of systemic therapy administered in the advanced / metastatic setting.

[0268] In various embodiments, the TNBC tumor expresses c-Met. In embodiments, only subjects with a TNBC tumor that expresses c-Met are treated, and subjects with tumors that do not express c-Met are excluded from treatment. In certain embodiments, the c-Met expressing TNBC tumor is histologically or cytologically confirmed locally advanced or metastatic, unresectable TNBC with progression following at least 1 prior line of systemic therapy administered in the advanced / metastatic setting.

[0269] In various embodiments, subjects having a TNBC tumor are treated without knowledge or assessment of TNBC tumor c-Met expression.

[0270] In specific embodiments, the TNBC tumor is histologically or cytologically confirmed locally advanced or metastatic, unresectable TNBC with progression following at least 1 prior line of systemic therapy administered in the advanced / metastatic setting, a 78 158929154.2therapeutically effective amount of 2.4 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to the human subject, the anti-c-Met ADC has an average DAR of about 6, and administration of the anti-c-Met ADC achieves PR in the human subject. In specific embodiments, the TNBC tumor is histologically or cytologically confirmed locally advanced or metastatic, unresectable TNBC with progression following at least 1 prior line of systemic therapy administered in the advanced / metastatic setting, a therapeutically effective amount of 3.0 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to the human subject, the anti-c-Met ADC has an average DAR of about 6, and administration of the anti-c-Met ADC achieves PR in the human subject. In specific embodiments, the TNBC tumor is histologically or cytologically confirmed locally advanced or metastatic, unresectable TNBC with progression following at least 1 prior line of systemic therapy administered in the advanced / metastatic setting, a therapeutically effective amount of 2.4 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to a plurality of human subjects, the anti-c-Met ADC has an average DAR of about 6, and administration of the anti-c-Met ADC provides an overall response rate that is greater than 25%. In specific embodiments, the TNBC tumor is histologically or cytologically confirmed locally advanced or metastatic, unresectable TNBC with progression following at least 1 prior line of systemic therapy administered in the advanced / metastatic setting, a therapeutically effective amount of 3.0 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to a plurality of human subjects, the anti-c-Met ADC has an average DAR of about 6, and administration of the anti-c-Met ADC provides an overall response rate that is greater than 25%.

[0271] In embodiments, subjects with tumors not meeting the criteria set forth in this section, (e.g., including but not limited to histologically or cytologically confirmed locally advanced or metastatic, unresectable with progression following at least 1 prior line of systemic therapy administered in the advanced / metastatic setting) are excluded from treatment. 7.3.10 Hormone Receptor-Positive / Human Epidermal Growth Factor Receptor 2-Negative Breast Cancer (“HR+ / HER2- BC”)

[0272] In another aspect, provided herein is a method of treating a hormone receptor- positive / human epidermal growth factor receptor 2-negative breast cancer tumor (“HR+ / HER2- BC”) tumor, comprising administering to a human subject or population of 79 158929154.2human subjects having said HR+ / HER2- BC tumor a therapeutically effective amount of ADC1, wherein ADC1 has the following structure:

[0273] wherein n is 2, 4, 6, 8, or 10, and wherein Ab is telisotuzumab, thereby treating said HR+ / HER2- BC tumor.

[0274] In a preferred embodiment, ADC1 is administered to the human patient once every three (3) weeks at a dose of 1.6 mg / kg, 2.4 mg / kg, 3.0 mg / kg, 3.5 mg / kg, 4.0 mg / kg, or 6.0 mg / kg. In a preferred embodiment, ADC1 is administered parenterally. In a preferred embodiment, the parenteral administration is intravenous administration. In a preferred embodiment, ADC1 is administered once every three weeks until disease progression, withdrawal of consent, or unacceptable toxicity.

[0275] In certain embodiments, the HR+ / HER2- BC tumor is histologically or cytologically confirmed locally advanced or metastatic, unresectable HR+ / HER2- breast cancer per ASCO / CAP criteria with progression following at least 1 endocrine therapy and a cyclin- dependent kinase (CDK) 4 / 6 inhibitor in the advanced / metastatic setting.

[0276] In various embodiments, the HR+ / HER2- BC tumor expresses c-Met. In embodiments, only subjects with a HR+ / HER2- BC tumor that expresses c-Met are treated, and subjects with tumors that do not express c-Met are excluded from treatment. In certain embodiments, the c-Met expressing HR+ / HER2- BC tumor is histologically or cytologically confirmed locally advanced or metastatic, unresectable HR+ / HER2- BC with progression following at least 1 prior line of systemic therapy administered in the advanced / metastatic setting.

[0277] In various embodiments, subjects having an HR+ / HER2- BC tumor are treated without knowledge or assessment of HR+ / HER2- BC tumor c-Met expression. 80 158929154.2

[0278] In specific embodiments, the HR+ / HER2- BC tumor is histologically or cytologically confirmed locally advanced or metastatic, unresectable HR+ / HER2- breast cancer with progression following at least 1 endocrine therapy and a cyclin-dependent kinase (CDK) 4 / 6 inhibitor in the advanced / metastatic setting, a therapeutically effective amount of 2.4 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to the human subject, the anti-c-Met ADC has an average DAR of about 6, and administration of the anti-c-Met ADC achieves PR in the human subject. In specific embodiments, the HR+ / HER2- BC tumor is histologically or cytologically confirmed locally advanced or metastatic, unresectable HR+ / HER2- breast cancer with progression following at least 1 endocrine therapy and a cyclin-dependent kinase (CDK) 4 / 6 inhibitor in the advanced / metastatic setting, a therapeutically effective amount of 3.0 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to the human subject, the anti-c-Met ADC has an average DAR of about 6, and administration of the anti-c-Met ADC achieves PR in the human subject. In specific embodiments, the HR+ / HER2- BC tumor is histologically or cytologically confirmed locally advanced or metastatic, unresectable HR+ / HER2- breast cancer with progression following at least 1 endocrine therapy and a cyclin-dependent kinase (CDK) 4 / 6 inhibitor in the advanced / metastatic setting, a therapeutically effective amount of 2.4 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks a plurality of human subjects, the anti-c-Met ADC has an average DAR of about 6, and administration of the anti-c-Met ADC provides an overall response rate that is greater than 25%. In specific embodiments, the HR+ / HER2- BC tumor is histologically or cytologically confirmed locally advanced or metastatic, unresectable HR+ / HER2- breast cancer with progression following at least 1 endocrine therapy and a cyclin-dependent kinase (CDK) 4 / 6 inhibitor in the advanced / metastatic setting, a therapeutically effective amount of 3.0 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to a plurality of human subjects, the anti-c-Met ADC has an average DAR of about 6, and administration of the anti-c-Met ADC provides an overall response rate that is greater than 25%.

[0279] In embodiments, subjects with tumors not meeting the criteria set forth in this section, (e.g., including but not limited to histologically or cytologically confirmed locally advanced or metastatic, unresectable HR+ / HER2- breast cancer with progression following at least 1 endocrine therapy and a cyclin-dependent kinase (CDK) 4 / 6 inhibitor in the advanced / metastatic setting) are excluded from treatment. 81 158929154.27.3.11 Head And Neck Squamous Cell Carcinoma (“HNSCC”)

[0280] In another aspect, provided herein is a method of treating a head and neck squamous cell carcinoma (HNSCC) tumor, comprising administering to a human subject or population of human subjects having said HNSCC tumor a therapeutically effective amount of ADC1, wherein ADC1 has the following structure:

[0281] wherein n is 2, 4, 6, 8, or 10, and wherein Ab is telisotuzumab, thereby treating said HNSCC tumor.

[0282] In a preferred embodiment, ADC1 is administered to the human patient once every three (3) weeks at a dose of 1.6 mg / kg, 2.4 mg / kg, 3.0 mg / kg, 3.5 mg / kg, 4.0 mg / kg, or 6.0 mg / kg. In a preferred embodiment, ADC1 is administered parenterally. In a preferred embodiment, the parenteral administration is intravenous administration. In a preferred embodiment, ADC1 is administered once every three weeks until disease progression, withdrawal of consent, or unacceptable toxicity.

[0283] In certain embodiments, the HNSCC tumor is histologically or cytologically confirmed locally advanced or recurrent / metastatic, unresectable HNSCC with progression following at least 1 prior line of systemic therapy in the advanced / metastatic setting.

[0284] In various embodiments, the HNSCC tumor expresses c-Met. In embodiments, only subjects with a HNSCC tumor that expresses c-Met are treated, and subjects with tumors that do not express c-Met are excluded from treatment. In certain embodiments, the c-Met expressing HNSCC tumor is histologically or cytologically confirmed locally advanced or metastatic, unresectable HNSCC with progression following at least 1 prior line of systemic therapy administered in the advanced / metastatic setting.

[0285] In various embodiments, subjects having an HNSCC tumor are treated without knowledge or assessment of HNSCC tumor c-Met expression. 82 158929154.2

[0286] In specific embodiments, the HNSCC tumor is histologically or cytologically confirmed locally advanced or recurrent / metastatic, unresectable HNSCC with progression following at least 1 prior line of systemic therapy in the advanced / metastatic setting, a therapeutically effective amount of 2.4 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to the human subject, the anti-c-Met ADC has an average DAR of about 6, and administration of the anti-c-Met ADC achieves PR in the human subject. In specific embodiments, the HNSCC tumor is histologically or cytologically confirmed locally advanced or recurrent / metastatic, unresectable HNSCC with progression following at least 1 prior line of systemic therapy in the advanced / metastatic setting, a therapeutically effective amount of 3.0 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to the human subject, the anti-c-Met ADC has an average DAR of about 6, and administration of the anti-c-Met ADC achieves PR in the human subject. In specific embodiments, the HNSCC tumor is histologically or cytologically confirmed locally advanced or recurrent / metastatic, unresectable HNSCC with progression following at least 1 prior line of systemic therapy in the advanced / metastatic setting, a therapeutically effective amount of 2.4 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to a plurality of human subjects, the anti-c-Met ADC has an average DAR of about 6, and administration of the anti-c-Met ADC provides an overall response rate that is greater than 25%. In specific embodiments, the HNSCC tumor is histologically or cytologically confirmed locally advanced or recurrent / metastatic, unresectable HNSCC with progression following at least 1 prior line of systemic therapy in the advanced / metastatic setting, a therapeutically effective amount of 3.0 mg / kg of the anti-c- Met ADC is administered intravenously every three weeks to a plurality of human subjects, the anti-c-Met ADC has an average DAR of about 6, and administration of the anti-c-Met ADC provides an overall response rate that is greater than 25%.

[0287] In embodiments, subjects with tumors not meeting the criteria set forth in this section, (e.g., including but not limited to histologically or cytologically confirmed locally advanced or recurrent / metastatic, unresectable HNSCC with progression following at least 1 prior line of systemic therapy in the advanced / metastatic setting) are excluded from treatment. 7.3.12 MET Gene Mutated Advanced Solid Cancers “mutMET”

[0288] In another aspect, provided herein is a method of treating a MET gene mutated advanced solid tumor, comprising administering to a human subject or population of human 83 158929154.2subjects having said MET gene mutated advanced solid tumor a therapeutically effective amount of ADC1, wherein ADC1 has the following structure:

[0289] wherein n is 2, 4, 6, 8, or 10, and wherein Ab is telisotuzumab, thereby treating said MET gene amplified advanced solid tumor.

[0290] In a preferred embodiment, ADC1 is administered to the human patient once every three (3) weeks at a dose of 1.6 mg / kg, 2.4 mg / kg, 3.0 mg / kg, 3.5 mg / kg, 4.0 mg / kg, or 6.0 mg / kg. In a preferred embodiment, ADC1 is administered parenterally. In a preferred embodiment, the parenteral administration is intravenous administration. In a preferred embodiment, ADC1 is administered once every three weeks until disease progression, withdrawal of consent, or unacceptable toxicity.

[0291] In various embodiments, the MET gene mutated advanced solid tumor expresses c- Met. In embodiments, only subjects with a MET gene mutated advanced solid tumor that expresses c-Met are treated, and subjects with tumors that do not express c-Met are excluded from treatment. In certain embodiments, the c-Met expressing MET gene mutated advanced solid tumor is a histologically or cytologically confirmed locally advanced or metastatic, unresectable MET gene mutated advanced solid tumor with progression following at least 1 prior line of systemic therapy administered in the advanced / metastatic setting.

[0292] In various embodiments, subjects having a MET gene mutated advanced solid tumor are treated without knowledge or assessment of MET gene mutated advanced solid tumor c- Met expression.

[0293] In certain embodiments, the MET gene mutated advanced solid tumor is an advanced histologically or cytologically confirmed solid tumor harboring MET mutations including: mutations in the tyrosine kinase domain, the juxtamembrane region and the extracellular domain (as locally determined by NGS or a validated qPCR on tissue). In embodiments, 84 158929154.2subjects who are not amenable to surgical resection and who have disease progression after at least one prior systemic therapy and / or who have no satisfactory alternative treatment options are treated. In embodiments, only subjects with MET gene mutated advanced solid tumors are treated, and those without such tumors are excluded from treatment. In embodiments, only subjects with MET gene mutated advanced solid tumors who are not amenable to surgical resection and who have disease progression after at least one prior systemic therapy and / or who have no satisfactory alternative treatment options are treated, and those not meeting these criteria are excluded from treatment.

[0294] In specific embodiments, the MET gene mutated advanced solid tumor is not amenable to surgical resection and had disease progression after at least one prior systemic therapy and / or no satisfactory alternative treatment options, a therapeutically effective amount of 2.4 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to the human subject, the anti-c-Met ADC has an average DAR of about 6, and administration of the anti-c-Met ADC achieves PR in the human subject. In specific embodiments, the MET gene mutated advanced solid tumor is not amenable to surgical resection and had disease progression after at least one prior systemic therapy and / or no satisfactory alternative treatment options, a therapeutically effective amount of 3.0 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to the human subject, the anti-c-Met ADC has an average DAR of about 6, and administration of the anti-c-Met ADC achieves PR in the human subject. In specific embodiments, the MET gene mutated advanced solid tumor is not amenable to surgical resection and had disease progression after at least one prior systemic therapy and / or no satisfactory alternative treatment options, a therapeutically effective amount of 2.4 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to a plurality of human subjects, the anti-c-Met ADC has an average DAR of about 6, and administration of the anti-c-Met ADC provides an overall response rate that is greater than 25%. In specific embodiments, the MET gene mutated advanced solid tumor is not amenable to surgical resection and had disease progression after at least one prior systemic therapy and / or no satisfactory alternative treatment options, a therapeutically effective amount of 3.0 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to a plurality of human subjects, the anti-c-Met ADC has an average DAR of about 6, and administration of the anti-c-Met ADC provides an overall response rate that is greater than 25%. 85 158929154.2

[0295] In embodiments, subjects with tumors not meeting the criteria set forth in this section, (e.g., including but not limited to not amenable to surgical resection and disease progression after at least one prior systemic therapy and / or no satisfactory alternative treatment options) are excluded from treatment.

[0296] In some embodiments, MET gene mutation is determined using a next generation sequencing assay (NGS). In some embodiments, MET gene mutation is detected using fragment length analysis (FLA). In an embodiment, NGS and FLA are used together. In embodiments, the MET gene mutation is detected using a DNA sample from the tumor. In embodiments, the MET gene mutation is detected using an RNA sample from the tumor. MET gene mutations include MET exon 14 skipping mutations, which are known to the person of skill in the art, as well as methods of detecting these mutations. Heydt., et al. Cancers (Basel).2023 Jun; 15(11): 2932, incorporated herein by reference in its entirety. 7.3.13 Therapeutic Endpoints

[0297] In various aspects and embodiments of a treatment method described herein, administration of the anti-c-Met ADC (e.g., ADC1) provides an overall response rate that is superior to that of the standard of care therapy(ies) for the tumor. In various aspects and embodiments of a treatment method described herein, administration of the anti-c-Met ADC (e.g., ADC1) provides an overall response rate that is greater than 25%, greater than 30%, greater than 35%, greater than 40%, greater than 45%, greater than 50%, greater than 55%, greater than 60%, greater than 65%, greater than 70%, greater than 75%, or greater than 80%.

[0298] In embodiments, subjects treated according to the disclosed methods experience a clinical benefit rate (“CBR”) of greater than 40%, greater than 45%, greater than 50%, greater than 55%, greater than 60%, greater than 65%, greater than 70%, greater than 75%, or greater than 80%.

[0299] In various aspects and embodiments of a treatment method described herein, administration of the anti-c-Met ADC (e.g., ADC1) exhibits an acceptable safety and tolerability profile.

[0300] In various aspects and embodiments of a treatment method described herein, administration of the anti-c-Met ADC (e.g., ADC1) achieves a partial response (PR) in the human subject. 86 158929154.2

[0301] In various aspects and embodiments of a treatment method described herein, administration of the anti-c-Met ADC (e.g., ADC1) achieves a complete response (CR) in the human subject.

[0302] In various aspects and embodiments of a treatment method described herein, administration of the anti-c-Met ADC (e.g., ADC1) achieves stable disease (SD) in the human subject.

[0303] In embodiments, subjects treated according to the disclosed methods experience progression free survival (“PFS”) of 3 months or greater than 3 months, 4 months or greater than 4 months, 5 months or greater than 5 months or 6 months or greater than 6 months.

[0304] In embodiments, subjects treated according to the disclosed methods experience duration of response (“DoR”) of 3 months or greater than 3 months, 4 months or greater than 4 months, 5 months or greater than 5 months or 6 months or greater than 6 months.

[0305] In various aspects and embodiments of a treatment method described herein, the anti- c-Met ADC (e.g., ADC1) is administered to the human subject intravenously.

[0306] In various aspects and embodiments, one or more or all of the eligibility criteria listed in Section 7.2.1 are used to determine whether a human subject is eligible for treatment. 7.4 Diagnostics 7.4.1 C-Met Expression

[0307] IHC is used to evaluate candidate patients for selection for treatment with the anti-c- Met ADC on the basis of observed c-Met expression levels in tumor tissue. In some embodiments, c-Met IHC is performed on at least one tumor tissue from the subject, wherein the at least one tumor tissue is selected from archival tumor tissue and / or fresh tumor.

[0308] c-Met specific immunohistochemistry (c-Met IHC) is contemplated as a means for determining c-Met-overexpression in tumor tissue of a candidate patient for treatment with the anti-c-Met ADC. For this purpose, IHC scores of 0, 1+, 2+, and 3+ describe the visual c- Met staining intensities for individual neoplastic cells from tumor tissue, according to: 0 = no staining 1+ = weak staining 2+ = moderate staining 3+ = strong staining. 87 158929154.2Typically, there are ~100 human cells in a 20x fixed field. IHC scoring as used herein refers to the intensity of membranous c-Met staining or the intensity of membrane + cytoplasmic c- Met staining.

[0309] In some embodiments, patients selected for treatment with the anti-c-Met ADC have c-Met-overexpression determined by IHC, wherein said IHC comprises the steps of: 1) staining the membrane or membrane + cytoplasm of neoplastic cells of the tumor with a diagnostic reagent specific for c-Met, and 2) scoring the intensity of membrane or membrane + cytoplasm staining, wherein IHC scoring is performed using values scaled to correspond to a score of 0, a score of 1+, a score of 2+, and / or a score of 3+, wherein said score of 0 corresponds to a minimal visual membrane or membrane + cytoplasm staining intensity of at or about the intensity of a negative control, said score of 3+ corresponds to a maximum visual membrane or membrane + cytoplasm staining intensity of at or about the intensity of a positive control, and said scores of 1+ and 2+ correspond to visual membrane or membrane + cytoplasm staining intensities of at or about 1 / 3, and of at or about 2 / 3, of the maximum visual membrane or membrane + cytoplasm staining intensity of the positive control, respectively.

[0310] In embodiments, subjects treated according to the present methods (including methods of treating subjects with the tumors set forth above in section 7.3) are those with tumors that exhibit a level of c-Met expression that is equal to or greater than a predetermined cutoff level of expression. The c-Met expression cutoff is expressed as a combination of a percentage and a minimum staining intensity. For example, a c-Met expression cutoff of ≥10% 1+ is met if at least 10% of the cells in a field of view exhibit IHC staining of 1 or more.

[0311] In embodiments, subjects with tumors are selected for treatment if the tumors meet the c-Met IHC cutoff of ≥10% 1+. In embodiments, subjects with tumors are selected for treatment if the tumors meet the c-Met IHC cutoff of ≥10% 2+. In embodiments, subjects with tumors are selected for treatment if the tumors meet the c-Met IHC cutoff of ≥10% 3+.

[0312] In embodiments, subjects with tumors are selected for treatment if the tumors meet the c-Met IHC cutoff of ≥25% 1+. In embodiments, subjects with tumors are selected for 88 158929154.2treatment if the tumors meet the c-Met IHC cutoff of ≥25% 2+. In embodiments, subjects with tumors are selected for treatment if the tumors meet the c-Met IHC cutoff of ≥25% 3+.

[0313] In embodiments, subjects with tumors are selected for treatment if the tumors meet the c-Met IHC cutoff of ≥50% 1+. In embodiments, subjects with tumors are selected for treatment if the tumors meet the c-Met IHC cutoff of ≥50% 2+. In embodiments, subjects with tumors are selected for treatment if the tumors meet the c-Met IHC cutoff of ≥50% 3+.

[0314] In embodiments, subjects with tumors are selected for treatment if the tumors meet the c-Met IHC cutoff of ≥75% 1+. In embodiments, subjects with tumors are selected for treatment if the tumors meet the c-Met IHC cutoff of ≥75% 2+. In embodiments, subjects with tumors are selected for treatment if the tumors meet the c-Met IHC cutoff of ≥75% 3+.

[0315] In embodiments, subjects with tumors are selected for treatment if the tumors meet the c-Met IHC cutoff of ≥90% 1+. In embodiments, subjects with tumors are selected for treatment if the tumors meet the c-Met IHC cutoff of ≥90% 2+. In embodiments, subjects with tumors are selected for treatment if the tumors meet the c-Met IHC cutoff of ≥90% 3+.

[0316] In embodiments, subjects with tumors are selected for treatment if the tumors meet the c-Met IHC cutoff of ≥100% 1+. In embodiments, subjects with tumors are selected for treatment if the tumors meet the c-Met IHC cutoff of ≥100% 2+. In embodiments, subjects with tumors are selected for treatment if the tumors meet the c-Met IHC cutoff of ≥100% 3+.

[0317] In embodiments, subjects not meeting the IHC cutoff are excluded from treatment. In embodiments, tumors from a population of subjects with tumors are assessed for IHC staning, and those meeting the chosen IHC cutoff are selected for treatment, while those not meeting the IHC cutoff are excluded from treatment.

[0318] Details on how to visualize and determine the level of c-Met overexpression are presented below and in Example 4. For purposes of this application, including the claims, the particular assay used in Example 4 is referred to as the “c-Met staining protocol.” Briefly, a c-Met IHC staining assay for c-Met overexpression was developed using the Ventana c-Met CONFIRM (SP44) kit (Catalog Number 790-4430), and is contemplated for use in the selection of patients for treatment with the anti-c-Met ADC. In this assay, tissue samples are stained with the Ventana anti-c-Met antibody and then scored by determining the percentages of neoplastic cells of the tumor tissue that stain at certain intensity levels from weak / low to strong / high (i.e., 0, 1+, 2+, to 3+). This assay produces staining of the c-Met protein both in 89 158929154.2the cytoplasm and in the cell membrane, of which the membranous staining or the membrane + cytoplasmic staining is used in IHC score determination.

[0319] If different c-Met IHC scoring results are obtained with different IHC methods, then the c-Met IHC scoring results determined with the methods described in Example 4 are those to be used in determining whether a particular embodiment falls within the scope of the embodiments. For example, for evaluating expression of the c-Met protein one would use the “c-Met staining protocol.” If the reagents used in this protocol are no longer available, another FDA-approved protocol for assessment of c-Met expression levels by IHC can be used.

[0320] c-Met IHC detection is a diagnostic technique providing for visualization of c-Met antigens after their localization with a primary anti-c-Met antibody. In some embodiments, the primary anti-c-Met antibody is selected from a mouse IgG, mouse IgM or a rabbit antibody. In some embodiments, IHC detection comprises direct visualization of a primary anti-cMet antibody. In some embodiments, IHC detection comprises indirect visualization of a primary anti-cMet antibody. In some embodiments, indirect visualization comprises a secondary antibody specific for the species of primary anti-cMet antibody. In some embodiments, indirect visualization further comprises a tertiary antibody that binds to the secondary antibody, wherein the tertiary antibody is conjugated to at least one enzyme. In some embodiments, indirect visualization further comprises a chromogen having a substrate specific for the at least one enzyme of the tertiary antibody. In some embodiments, the chromogen produces a detectable precipitate, preferably wherein the precipitate is detectable by visualization and / or colorimetric shift. In certain embodiments, the substrate is hydrogen peroxide. In certain embodiments, the chromogen is 3, 3’–diaminobenzidine tetrahydrochloride (DAB).

[0321] In some embodiments, expression of c-Met is determined using an OptiView DAB IHC Detection Kit (Ventana Catalog Number 760-700). Optiview kits use an indirect method to visualize specific mouse and rabbit primary antibodies bound to an antigen by depositing a brown colored precipitate.

[0322] In some embodiments, IHC detection of c-Met expression comprises the step of staining tumor tissue that is frozen, formalin-fixed, and / or paraffin-embedded. In some embodiments, tumor tissue staining is performed via slide staining device. As contemplated, such a slide staining device automates a slide staining step, for example, washing the slide to 90 158929154.2remove unbound material after an antibody incubation step and / or applying a coverslip to the slide. In some embodiments, the slide staining device is a VENTANA®slide staining device. In some embodiments, the slide staining device is a VENTANA®BenchMark Series instrument (i.e., a BenchMark ULTRA IHC / ISH System).

[0323] Formalin-fixed, paraffin-embedded tissues are suitable for use with OptiView DAB IHC Detection Kit and VENTANA®BenchMark Series instruments. In some embodiments, preparation of tumor tissue for IHC detection comprises the step of contacting the tumor tissue with a fixative. In some embodiments, a formalin-based fixative is used, e.g., 10% neutral buffered formalin (NBF).

[0324] To minimize variability of visualization results, tumor tissue section thickness, fixation type and duration may be optimized. In some embodiments, tumor tissue sections are of a thickness of about 2 μm to about 6 μm. In some embodiments, tumor tissue sections are of a thickness of about 2, about 3, about 4, about 5, or about 6 μm. Slide heating is contemplated for drying tumor tissue sections after slide mounting, or to enhance tissue adhesion to the glass microscope slides. In some embodiments, a slide containing the tumor tissue section is heated, preferably it is baked. In some embodiments, the slides are heated for between 2 and 24 hours at 60°C ± 5°C. Avoid excessive heating of the tumor tissue, as it may decrease antigen availability. In some embodiments, the slides are contacted with cold acetone (i.e., 4-8°C) for ten minutes. In some embodiments, the slides are air dried for at least 30 minutes following contact with cold acetone, preferably overnight.

[0325] A positive tissue control is contemplated as being run with the c-Met IHC staining procedure. The positive tissue control can be, for example, a tumor tissue or non-neoplastic gallbladder tissue. Some or all of a positive tissue control will feature strong staining. A positive tissue control may contain both positive and negative staining, and serve as both the positive and negative control tissue. Cellular components that do not stain should demonstrate an absence of specific staining, which provides an indication of background staining. In some embodiments, the same tissue used for the positive tissue control is used as the negative tissue control. In some embodiments, the tissue for the positive or negative control is prepared in a manner identical to the test tissue.

[0326] A negative control aids interpretation of c-Met IHC scores. In some embodiments, a negative reagent control is used in place of the primary anti-c-Met antibody to evaluate nonspecific staining. In some embodiments, the negative control reagent is the diluent alone. 91 158929154.2In preferred embodiments, the incubation period for the negative reagent control equals the incubation period for the primary antibody.

[0327] The OptiView DAB IHC Detection Kit (Ventana Catalog Number 760-700) as contemplated for the invention causes a brown colored reaction product to precipitate at or about the c-Met antigen sites localized by the primary anti-c-Met antibody.

[0328] In some embodiments, detection of c-Met expression by IHC is performed by a qualified pathologist experienced in immunohistochemical procedures. In some embodiments, detection of c-Met expression occurs after the step of evaluating the positive and negative controls. Staining of negative reagent controls are noted, and these results compared to the stained material to verify that the visualization observed is not due to nonspecific interactions. Positive tissue control is examined to verify proper functioning of reagents. If the positive tissue control fails to demonstrate positive staining, results with the test specimens should be considered invalid for purposes of the methods of treatment disclosed herein. Negative tissue control should be examined after the positive tissue control to verify the specific labeling of the target antigen by the primary antibody. The absence of specific staining in the negative tissue control confirms the lack of anti-c-Met primary antibody binding. If specific staining occurs in the negative tissue control, results with the test specimens should be considered invalid for the purposes of the methods of treatment disclosed herein. Nonspecific staining may have a diffuse appearance. Sporadic light staining may also indicate excessive formalin fixation of cells. Necrotic or degenerated cells may stain nonspecifically.

[0329] In some embodiments of the methods of treatment, intact cells of the tumor tissue are assayed for c-Met expression by IHC. Tissue sample biopsies, resections or cytology samples of the patient are examined after controls, as described herein, with staining intensity assessed within the context of any non-specific background staining of the controls (i.e., the negative tissue control, and the negative reagent control.) The morphology of cells of the tissue sample should also be examined by a qualified pathologist experienced in immunohistochemical procedures. In some embodiments, the tissue sample is contacted with a hematoxylin or eosin stain.

[0330] In some embodiments, patients selected for treatment have c-Met expression determined for tumor tissue by c-Met IHC assay, wherein the c-Met IHC assay is the c-Met staining protocol. In some embodiments, the c-Met IHC assay is performed on an automated 92 158929154.2slide stainer. In some embodiments, the c-Met IHC assay comprises the steps of: 1) applying a bar code label to a slide having tumor tissue, wherein the bar code corresponds to one or more automated IHC protocols to be performed by an automated slide stainer; 2) loading a primary anti-c-Met antibody, at least one negative reagent control, and / or one or more detection reagents onto the automated slide stainer; 3) loading at least one slide having tumor tissue onto the automated slide stainer; 4) running the automated slide stainer according to the one or more automated IHC protocols, thereby staining c-Met tumor tissue on the slides; and 5) detecting and scoring the c-Met IHC staining of the slides. In some embodiments, the automated slide stainer is a Ventana BenchMark series instrument, optionally a Ventana Benchmark Ultra automated staining instrument. In some embodiments, the bar code corresponds to an SP44 IHC protocol. In some embodiments, the SP44 IHC protocol is selected from a Deparaffinization protocol, a Cell Conditioning protocol (i.e., Ventana Catalog No.950-224), an Antibody protocol (i.e., for SP44: Ventana Catalog No.790-4430, or for Rabbit Monoclonal Negative Control Ig: Ventana Catalog No.790-4795), a Detection protocol (i.e., for OptiView DAB IHC Detection Kit: Ventana Catalog No.760-700), or a Counterstain protocol (i.e., for hematoxylin II: Ventana Catalog No.790-2208, or for bluing reagent: Ventana Catalog No.760-2037). In some embodiments, the primary anti-cMet antibody is the SP44 antibody. In some embodiments the one or more negative reagent controls is a negative control immunoglobulin. In some embodiments, the one or more detection reagents are from an OptiView detection kit, optionally selected from Reaction Buffer (Ventana Catalog No.950-300), Ultra Liquid Coverslip (Ventana Catalog No.650- 210), or EZ Prep (Ventana Catalog No.950-102). 7.4.2 MET Amplification 7.4.2.1 Detection of MET Gene Amplification

[0331] In embodiments, the amplification of the MET gene is due to aneuploidy. In embodiments, the amplification of the MET gene is a focal amplification of the MET gene. A focal amplification is an amplification of a portion of a chromosome and is distinguished from amplification due to aneuploidy. A normal diploid cell without an amplified MET gene will contain two copies of the MET gene. In an embodiment, the presence of more than 2 copies of the MET gene in a cell indicates that the MET gene is amplified. In embodiments, the presence of 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 10 or more, 15 or more, or 20 or more copies of the MET gene in a cell indicates that the MET gene is amplified. 93 158929154.2

[0332] Several techniques are known to one of ordinary skill in the art for assessing amplification of the MET gene and can be used to detect the number of MET copies in tumor cells. Fluorescence in situ hybridization (FISH) uses fluorescent-labeled probes that specifically bind to the MET gene region on chromosomes, allowing for visualization of the gene copy number (GCN) under a microscope. Chromogenic in situ hybridization (CISH) is a similar technique to FISH, but instead of fluorescent probes, chromogenic probes are used that produce a visible signal under the microscope. Polymerase chain reaction (PCR) amplifies specific regions of DNA using specific primers. The amplification products can then be quantified to determine the GCN of the MET gene. Next generation sequencing (NGS) can provide information on the GCN of the MET gene as well as other genetic alterations, such as mutations or rearrangements.

[0333] MET FISH is contemplated as a means for determining MET gene amplification in the tumor of a candidate patient for treatment with ADC1. In an embodiment, the MET FISH assay is a dual-color, spot-counting FISH assay utilizing orange probe for the MET gene in locus 7q31.2 and green probe for CEP7 to detect allelic copy numbers at the corresponding loci. Formalin-fixed, paraffin-embedded (FFPE) slides are processed, hybridized with the MET and CEP7 probes with a buffer, and washed. Tumor cells are evaluated based on MET / CEP7 cutoff criteria.

[0334] Other methods of determining gene amplification are also contemplated. Gene copy number can be determined by, for example, next generation sequencing (NGS), or PCR techniques as means for determining MET gene amplification in the tumor of a candidate patient for treatment with ADC1. In an embodiment, the assay utilizes NGS. A non-limiting example of an NGS tissue biopsy test includes Foundation Medicine F1CDxm which can identify MET amplification from tumor tissues in patients with MET copy number ≥ (4+ploidy), e.g. in diploid, MET amplified is defined as MET copy number ≥ 6.

[0335] In one embodiment, the method of treatment comprises the steps of determining the level of MET amplification within tumor. In an embodiment, MET amplification is determined by MET FISH. In an embodiment, amplification is determined by performing an amplification assay, such as MET FISH, on tumor tissue (i.e., obtained from a biopsy, resection or cytology sample; the tumor tissue can be archival tumor tissue or fresh tumor tissue) from the subject, and further comprising the step of determining whether the tumor tissue exhibits negative MET amplification or positive MET amplification. In some embodiments, the MET FISH is performed according to the MET FISH Protocol. In some 94 158929154.2embodiments, MET FISH is performed on at least one tumor tissue from the subject, wherein the at least one tumor tissue is selected from archival tumor tissue and / or fresh tumor tissue. The level of MET amplification in the tumor is taken to be that of its sampled tissue.

[0336] In one embodiment, MET amplification within the tumor is determined by performing MET FISH on neoplastic cells from tumor tissue from the subject, and determining whether the neoplastic cells exhibit i) positive MET gene amplification or ii) negative MET gene amplification; based on the results of the MET FISH assay. In one embodiment, the MET FISH is performed according to the MET FISH Protocol, described herein.

[0337] Circulating tumor DNA (ctDNA) can also be used to determine MET amplification. In embodiments, a blood sample is taken from a subject and tested for the presence of MET amplified ctDNA. In embodiments, the ctDNA is tested for MET amplification by a PCR based assay, or an NGS based assay. A non-limiting example of NGS liquid biopsy test (ctDNA) is Guardant360 CDx, which can detect focal MET amplification from ctDNA in blood with plasma MET Copy Number (CN) ≥ 2.16. The plasma copy number is a combination of germline copy number, tumor tissue copy number, and mutant allele fraction (MAF).

[0338] In embodiments, subjects treated according to the present methods (including methods of treating subjects with the tumors set forth above in section 7.3) are those with tumors that exhibit MET amplification. In embodiments, subjects with tumors are selected for treatment if the tumors exhibit MET amplification.

[0339] In embodiments, subjects with tumors not exhibiting MET amplification are excluded from treatment. In embodiments, tumors from a population of subjects with tumors are assessed for MET amplification, and those exhibiting MET amplification are selected for treatment, while those not exhibiting MET amplification are excluded from treatment.

[0340] In embodiments, testing that meets the specified MET amplification cutoffs is performed in a College of American Pathologists (CAP) accredited and / or Clinical Laboratory Improvement Amendments (CLIA) certified or equivalently accredited lab. 7.4.2.2 Determination of MET Gene Amplification Status

[0341] Negative MET gene amplification is defined by a MET / CEP7 signal ratio of <1.8 from tumor tissue assessed by a MET FISH assay, for example the MET FISH Protocol. 95 158929154.2Positive MET gene amplification is defined by a MET / CEP7 signal ratio of 1.8 or greater from tumor tissue assessed by a MET FISH assay, for example the MET FISH Protocol. Low MET gene amplification is defined by a MET / CEP7 signal ratio of greater than or equal to 1.8 through 2.2 from tumor tissue assessed by a MET FISH assay, for example the MET FISH Protocol. Intermediate MET amplification is defined by a MET / CEP7 signal ratio of >2.2 to <5.0 from tumor tissue assessed by a MET FISH assay, for example the MET FISH Protocol. High MET amplification is defined by a MET / CEP7 signal ratio of 5.0 or greater from tumor tissue assessed by a MET FISH assay, for example the MET FISH Protocol. These amplification cutoffs are summarized in the following table:

[0342] Table 1: Amplification cutoffs summarized - MET / CEP7 signal ratio.

[0343] In some embodiments, Genome Copy Number (GCN) is determined by NGS. In embodiments, negative MET amplification is defined by a GCN of < 5 from tumor tissue assessed by an NGS assay, and positive MET amplification is defined by a GCN of ≥ 5. Low MET amplification is defined by a GCN of ≥ 5 and <10 from tumor tissue assessed by an NGS assay. High MET amplification is defined by a GCN of ≥ 10 from tumor tissue assessed by an NGS assay. These amplification cutoffs are summarized in the following table:

[0344] Table 2: Amplification cutoffs summarized - GCN96 158929154.2

[0345] It is within the ability of persons of skill in the art to compare and correlate different types of gene amplification assays to identify patients with the same or substantially the same degree of MET amplification. For example, it is within the skill in the art to correlate non- FISH assay results (e.g., NGS or CISH) to the MET FISH assay results so that the non-FISH assay could be used to identify subjects that, if assayed by the MET FISH assay, would have a MET / CEP7 signal ratio of 1.8 or greater, or a MET / CEP7 signal ratio of greater than or equal to 1.8 through 2.2, or a MET / CEP7 signal ratio of >2.2 to <5.0, or a MET / CEP7 signal ratio of 5.0 or greater.

[0346] In certain embodiments, subjects having tumor tissue exhibiting negative MET amplification are excluded from treatment with the anti-cMet-ADC. In certain embodiments, subjects having tumor tissue exhibiting negative focal MET amplification are excluded from treatment with the anti-cMet-ADC.

[0347] In some embodiments, patients selected for treatment with anti-cMet-ADC have tumor tissue having positive MET amplification. In some embodiments, patients selected for treatment with anti-cMet-ADC have tumor tissue having positive focal MET amplification.

[0348] In certain embodiments, subjects having GEA tumor tissue exhibiting negative MET amplification are excluded from treatment with the anti-cMet-ADC. In certain embodiments, subjects having GEA tumor tissue exhibiting negative focal MET amplification are excluded from treatment with the anti-cMet-ADC.

[0349] In some embodiments, patients selected for treatment with anti-cMet-ADC have GEA tumor tissue having positive MET amplification. In some embodiments, patients selected for treatment with anti-cMet-ADC have GEA tumor tissue having positive focal MET amplification. 7.4.3 EGFR Status

[0350] In embodiments, patients selected for treatment have MET amplification positive non-squamous NSCLC that is EGFR wild-type. In some embodiments, the EGFR status (wild-type or mutant) of the NSCLC is detected by an FDA-approved test. One such test uses real-time polymerase chain reaction (PCR) to identify mutations in exons 18, 19, 20 and 21 of the EGFR gene. The test has been clinically validated in multiple clinical trials as a 97 158929154.2companion diagnostic (CDx) for both first- and second-line EGFR TKI therapy in patients with advanced NSCLC (Heeke, et al., (2019) Clinical Lung Cancer, 21 (1): 56-65).

[0351] Next generation sequencing (NGS) can also be used to detect EGFR mutations. A number of companies have FDA approved CDx assays to detect EGFR mutations, including Foundation One CDx, Thermo Fisher Oncomine NSCLC and Guardant 360CDx. See also Ding et al., (2019) Thoracic Cancer 10: 1879-1884 discussing the use of the Thermo Fisher Oncomine NSCLC assay. An actionable EGFR mutation is an EGFR mutation that is targetable with an available anticancer treatment. In an embodiment, the absence of an actionable EGFR mutation indicates that the NSCLC is EGFR wild-type. In another embodiment, the absence of an EGFR exon 19 deletion and an EGFR L858R mutation indicates that the NSCLC is EGFR wild-type. In another embodiment, the absence of an EGFR exon 19 deletion and an EGFR L858R mutation, and one or more of an EGFR exon 20 insertion, an EGFR L861Q mutation, an EGFR G719X mutation, and an EGFR S768I mutation indicates that the NSCLC is EGFR wild-type. In another embodiment, the absence of an EGFR exon 19 deletion, an EGFR L858R mutation, and an EGFR exon 20 insertion indicates that the NSCLC is EGFR wild- type. In another embodiment, the absence of an EGFR exon 19 deletion, an EGFR L858R mutation, an EGFR exon 20 insertion, an EGFR L861Q mutation, an EGFR G719X mutation, and an EGFR S768I mutation indicates that the NSCLC is EGFR wild-type. 8. EXAMPLES

[0352] The following Examples, which highlight certain features and properties of the exemplary embodiments of the methods described herein are provided for purposes of illustration. 8.1 Example 1 – ADC-1 DAR

[0353] The DAR profile for a composition comprising a plurality of ADC1 species (referred to herein as the ADC1 composition) was determined using reduced reversed phase liquid chromatography (r-RPLC). The protein was reduced into its light and heavy chain subunits using dithiothreitol. The reduced protein subunits interacted with the immobilized hydrophobic ligands of the chromatography column resin, which allowed for separation and quantitation of the light and heavy chains with different drug loads. Dual wavelength detection at 280 nm and 370 nm allowed for the differential of conjugated and non- conjugated light and heavy chains. The chromatograms are provided in FIG.1. 98 158929154.2

[0354] Dual wavelength detection at 280 nm and 370 nm was used to calculate a weighted average of the individual protein subunits conjugated to different drug loads based on corrected peak area (CPA) using the following equation:

[0355] The r-RPLC method determined the average DAR for the ADC1 composition is within the range of DAR 5.4 to 6.6.

[0356] The DAR distribution for the ADC1 composition was characterized by intact native mass spectrometry using a size exclusion chromatography (SEC) coupled with a Waters Synapt G2-SI high-resolution quadrupole time-of-flight mass spectrometer (QTOF-MS). Non-denaturing mobile phase and gentle ionization conditions allowed for the analysis and determination of drug-loading of the intact ADC1 antibody-drug-conjugate. The resulting mass spectrometric data was deconvoluted using a commercial advanced maximum entrophy (MaxEnt) algorithm to determine the drug-to-antibody ratio. A deconvoluted mass spectrum for the ADC1 composition is provided as FIG.2, which shows the most prevalent ADC1 species has n = 6. 8.2 Example 2-Phase 1 First-in-Human Study Aiming to Evaluate the Safety, Pharmacokinetics (PK), and Efficacy of the ADC1

[0357] Disclosed herein is an on-going Phase 1 first-in-human study aiming to evaluate the safety, pharmacokinetics (PK), and efficacy of the ADC1 composition described in Example 1, in adult subjects with advanced solid tumors. Primary objectives of the study are to evaluate the safety, tolerability, and PK of the ADC1 composition and to determine the recommended Phase 2 dose (RP2D) of the ADC1 composition administered as monotherapy, and to evaluate the efficacy of the ADC1 composition in subjects with the following advanced solid tumors: non-squamous non-small cell lung cancer (NSCLC), squamous NSCLC, gastroesophageal junction adenocarcinoma (GEA), and colorectal cancer (CRC). Approximately 500 subjects are enrolled in the Phase 1 study.

[0358] This ongoing study includes a monotherapy dose escalation of the ADC1 composition in advanced solid tumors (Part 1), and a monotherapy dose expansion of the ADC1 composition in the following advanced solid tumor indications: Biomarker selected: c- Met-intermediate / high non-squamous NSCLC with wildtype epidermal growth factor 99 158929154.2receptor (EGFR)-expression (EGFR-wt NSCLC) (Part 2i), c-Met-intermediate / high non- squamous NSCLC with mutated EGFR-expression (EGFR-mu NSCLC) (Part 2ii), c-Met overexpressing (OE) squamous NSCLC (Part 2iii), and c-Met OE GEA (Part 3). Unselected: c-Met unselected CRC (Part 4). Other monotherapy dose expansion studies of the ADC1 composition include MET-amplified selected advanced solid tumors (Part 5) and MET- mutation selected advanced solid tumors (Part 6). Combination studies include: CRC combination with a safety lead-in (Part 7a) of the ADC1 composition in combination with bevacizumab in advanced CRC and a dose optimization expansion (Part 7b) of ADC1 composition in combination with bevacizumab compared with TAS-102 (standard-of-care comparator) in combination with bevacizumab in unresectable mCRC subjects who are MSS or pMMR, BRAF V600E wild-type and have progressed after fluoropyrimidine (e.g., 5- fluorouracil or capecitabine), oxaliplatin and irinotecan

[0359] In Part 1, subjects with advanced solid tumor characterized by MET amplification across multiple indications are enrolled, including cholangiocarcinoma, ovarian cancer, colorectal cancer (CRC), non-small cell lung cancer (NSCLC), and breast cancer. Part 1 also investigates gastric / gastroesophageal junction adenocarcinoma (GEA), head and neck squamous cell carcinoma (HNSCC), and renal cell carcinoma (RCC).

[0360] In the study, the ADC1 composition is administered as an intravenous (IV) infusion once every 21 days (Q3W) in 21-day cycles until disease progression, withdrawal of consent, or unacceptable toxicity for up to 24 months within the context of this study. For the combination study Part 7a, approximately 60 subjects receive the ADC1 composition with bevacizumab once every 21 days (Q3W) in 21-day cycles. For Part 7b, approximately 20 subjects receive TAS-102 in combination with bevacizumab on a 28-day cycle with bevacizumab and administered once every 14 days (Q2W), and TAS-102 is administered twice daily on D1-5 and D8-12 of each 28-day cycle. The maximum treatment duration is two years.

[0361] A summary of the arms and interventions of the study is shown in Table 1.

[0362] Table 1 Summary of the arms and interventions.100 158929154.2101 158929154.28.2.1 Key Eligibility Criteria: (1) Male or female subjects, at least 18 years old (2) Histologic malignant solid tumor diagnosis (WHO criteria) (3) Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 (4) For Part 1 only - history of advanced solid tumor that has progressed on all standard of care therapy and is not amenable to surgical resection or other approved therapeutic options that have demonstrated clinical benefit (5) For Part 2 only – history of advanced c-Met OE non-squamous EGFR-wt or EGFR- muor history of advanced c-Met OE squamous NSCLC that have progressed after treatment with at least: • Platinum-based chemotherapy and an immune checkpoint inhibitor and / or appropriate targeted therapy, if applicable, for non-squamous EGFR-wt and squamous NSCLC (parts 2i and 2iii) • Platinum-based chemotherapy doublet and / or tyrosine kinase inhibitor(s) (TKI[s]) for non-squamous EGFR-muNSCLC (part 2ii) Subjects should have no more than 2 lines of prior cytotoxic chemotherapy excluding adjuvant therapy and must have advanced NSCLC that is not amenable to surgical resection or other approved therapeutic options, including immunotherapies, that have demonstrated clinical benefit. (6) For Part 3 only – history of advanced histopathologically or cytologically confirmed diagnosis of c-Met OE GEA that has progressed after treatment with at least 1 prior cytotoxic chemotherapeutic regimen for locally advanced or metastatic disease and have not received more than 2 prior lines of cytotoxic chemotherapy regimens and that is not amenable to surgical resection. Subjects must have progressed on: • If applicable, an immune checkpoint inhibitor 102 158929154.2• If applicable, appropriate available therapies, including HER2-directed therapies. (7) For Part 4 only - Subjects with history of advanced histopathologically or cytologically confirmed CRC that does not harbor the BRAF V600E mutation and is not dMMR+ / MSI-Hi with progression on: • A fluoropyrimidine (e.g., 5-fluorouracil or capecitabine) • Oxaliplatin • Irinotecan • If applicable, anti-EGFR (including, but not limited to cetuximab or panitumumab) • If applicable, anti-vascular endothelial growth factor (VEGF) monoclonal antibody (including but not limited to bevacizumab, ramucirumab, or aflibercept) • If applicable, targeted therapy • Subjects who are considered ineligible for or are intolerant of standard therapy per investigator are eligible. Prior treatment with Lonsurf or Regorafenib is also acceptable. (8) For Part 5 only – subjects with advanced histologically or cytologically confirmed solid tumors characterized by MET amplification who are not amenable to surgical resection and who have disease progression after at least one prior systemic therapy and / or who have no satisfactory alternative treatment options. • Subjects who are intolerant to standard treatment are eligible. (9) For Part 6 only – Subjects with advanced histologically or cytologically confirmed solid tumors harboring MET mutations including: mutations in the tyrosine kinase domain, the juxtamembrane region and the extracellular domain (as locally determined by next-generation sequence (NGS) or a validated qPCR on tissue), who are not amenable to surgical resection and who have disease progression after at least one prior systemic therapy and / or who have no satisfactory alternative treatment options. • Subjects who are intolerant to the standard treatment are eligible. 103 158929154.2(10) For Part 7 (CRC combination) only: Subjects with history of advanced histopathologically or cytologically confirmed CRC that does not harbor the mutation and are not dMMR+ / MSI-H with progression on: • A fluoropyrimidine (e.g., 5-fluorouracil or capecitabine) • Oxaliplatin • Irinotecan • If applicable, anti-EGFR (including, but not limited to cetuximab or panitumumab) • If applicable, anti-vascular endothelial growth factor (VEGF) monoclonal antibody (including but not limited to bevacizumab, ramucirumab, or aflibercept) • If applicable, targeted therapy Subjects who are considered ineligible for or are intolerant of standard therapy per investigator are eligible. Subjects treated previously with TAS-102 or regorafenib are not eligible. (11) Life expectancy ≥ 3 months, in the opinion of the investigator. (12) Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1. (13) Subjects should have laboratory values meeting the following criteria: • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3.0 × the upper limit of normal (ULN) within 7 days before Cycle 1, Day 1 dosing; • For subjects with liver metastases: AST and ALT ≤ 5.0 × ULN; • Estimated creatinine clearance ≥ 30 ml / min as calculated by the modified Cockcroft-Gault formula; • Total bilirubin ≤ 1.5 × ULN within 7 days before Cycle 1, Day 1 dosing (subjects with documented Gilbert's syndrome may have a total bilirubin ≤ 3 x ULN); • Absolute neutrophil count (ANC) ≥ 1,500 / mm3(with no granulocyte-colony stimulating factor [G-CSF] in the last 10 days); 104 158929154.2• Platelet count ≥ 100,000 / μL (with no platelet transfusion in the last 14 days); • Hemoglobin ≥ 8 g / dL (with no red blood cell transfusion in the past 14 days) • Albumin ≥ 3g / dL (14) No history of interstitial lung disease (ILD) or pneumonitis that required treatment with systemic steroids, nor any evidence of active ILD or pneumonitis. (15) No history of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis. (16) No history of clinically significant, intercurrent lung-specific illnesses including, but not limited to: • Underlying pulmonary disorder (i.e., pulmonary emboli within 3 months of the study enrollment, severe asthma, severe COPD, restrictive lung disease, pleural effusion, dependence on supplemental oxygen etc.) • Any autoimmune, connective tissue or inflammatory disorders with documented or suspicious pulmonary involvement at screening (i.e., rheumatoid arthritis, Sjogren's, sarcoidosis etc.), and prior pneumonectomy. (17) For Part 7 only: Prior TAS-102 or Regorafenib treated subjects are not eligible. 8.2.2 Pharmacokinetic Analysis

[0363] Whole blood samples are collected into appropriately labeled tubes and processed. Serum concentrations of ADC1 (total antibody and ADC), plasma concentrations of the unconjugated Top1 inhibitor payload, and relative titers of serum ADC1 anti-drug antibody (ADA) are determined using validated methods.

[0364] This Phase 1 study was initiated and is ongoing. The dose escalation scheme is shown in FIG.3, and the monotherapy dose expansion design is shown in FIG.4. Initial results are described in Example 3. 8.3 Example 3: Dose Escalation Results From a First-in-Human Study of ADC1, a Novel C-Met–Targeting Antibody-Drug Conjugate, in Advanced Solid Tumors

[0365] As of April 2023, 57 patients have been enrolled in the dose escalation study with a median follow-up of 6.5 months. Median age was 58 years (range, 34–79), 25 (54%) patients were male, and the cancer types included CRC (n=27), NSCLC (n=5), GEA (n=7), and MET gene amplified (n=11). The median number of prior treatment lines was 5 (1–13). The ADC1 105 158929154.2composition described in Example 1 demonstrated a tolerable safety profile as shown in Table 2:

[0366] Table 2: Safety profile of the ADC1 composition at below MTD and all doses collected from clinical study as of April 2023ILD, interstitial lung disease; MTD, maximum tolerated dose; TEAE, treatment-emergent adverse event.

[0367] Initial PK data indicates a greater than dose proportional ADC exposure with a half- life of 5–8 days, and dose-proportional payload exposure with a half-life of 6–12 days. The 106 158929154.2PK profiles of the ADC1 composition as compared with Top1i is shown in FIGS.5A and 5B. The PK parameters at the maximum tolerated dose (3 mg / kg) are shown in Table 3.

[0368] Table 3: PK profile of the ADC1 composition at MTD collected in clinical study as of April 2023 PK parameterTop1i payloadMedian Tmax2h (min: 0.25h, max: 24h) 24h (min: 24h, max: 48h) Cmaxa61.5 ug / mL (%CV: 22) 0.32 ng / mL (%CV: 24) AUCinfa8270 µg●h / mL (%CV: 46) 128 ng●h / mL (%CV: 58)aReported as geometric mean (%CV). ADC, antibody-drug conjugate; AUCinf, area under the plasma / serum concentration curve vs time; Cmax, maximum observed plasma / serum concentration; CV, coefficient of variation; MTD, maximum tolerated dose; PK, pharmacokinetic; Tmax, time to reach maximum observed concentration; Top1i, topoisomerase 1 inhibitor.

[0369] Clinical activity was observed with the ADC1 composition as demonstrated by Table 4. FIGS.6A and 6B show the percentage change in target lesion measurement from baseline over time in all patients (A; N=57) and patients with CRC (B; N=27).

[0370] Table 4: Clinical activity of the ADC1 composition observed in clinical study as of April 2023 107 158929154.2ADC1 Monotherapy, Q3W 1.6 2.4 3.0 3.5 4.0 6.0 mg / kg mg / kg mg / kg mg / kg mg / kg mg / kg Overall N=3 N=16 N=18 N=6 N=9 N=5 N=57 Objective Response Rate, n (%) CR 0 0 0 0 0 0 0 PR 0 5 (31.3) 7 (38.9) 0 1 (11.1) 1 (20.0) 14 (24.6) SD 2 (66.7) 6 (37.5) 8 (44.4) 3 (50.0) 7 (77.8) 3 (60.0) 29 (50.9) PD 1 (33.3) 4 (25.0) 1 (5.6) 1 (16.7) 1 (11.1) 0 8 (14.0) Incomplete Data 0 1 (6.3) 2 (11.1) 2 (33.3) 0 1 (20.0) 6 (10.5) (NE + Not assessed) 1.6 2.4 3.0 3.5 4.0 6.0 mg / kg mg / kg mg / kg mg / kg mg / kg mg / kg Overall N=3 N=16 N=18 N=6 N=9 N=5 N=57 Best Overall Response, n (%) CR 0 0 0 0 0 0 0 PR 0 5 (31.3) 7 (38.9) 2 (33.3) 2 (22.2) 1 (20.0) 17 (29.3) SDc 2 (66.7) 6 (37.5) 8 (44.4) 116.7) 6 (67.7) 3 (60.0) 26 (45.6) PD 1 (33.3) 4 (25.0) 1 (5.6) 1 (16.7) 1 (11.1) 0 8 (14.0) Not Evaluable (NE) 0 0 0 1 (16.7) 0 0 1 (1.8) Not Assessedd 0 1 (6.3) 2 (11.1) 1 (16.7) 0 1 (20.0) 5 (8.8)

[0371] The overall response rates (n / N) by dose and disease are summarized in Table 5.

[0372] Table 5. Overall response rates (n / N) by dose and disease observed in clinical study as of April 2023108 158929154.28.4 Example 4: c-Met Staining Protocol

[0373] The following assay was developed to determine the suitability of a candidate patient having NSCLC for selection to be treated with an anti-cMet ADC. An IHC staining assay for determining c-Met-overexpression was developed using the Ventana c-Met CONFIRM (SP44) kit and c-Met SP44 OptiView IHC Staining Assay.

[0374] This assay and aspects of its protocol are suitable for use in the pre-screening of patients having NSCLC for treatment with an anti-cMet ADC. 8.4.1 Materials and Methods Specimen Preparation

[0375] Routinely processed, formalin fixed, paraffin embedded tumor tissues were thin- sectioned at about 4 microns, and floated onto positively charged glass slides. Tissue was fixed using 10% neutral buffered formalin. Slides were stained immediately after sectioning, to avoid time-dependent reduction of antigenicity. Immunohistochemistry procedure

[0376] Immunohistochemistry (IHC) for c-Met was performed on the Ventana BenchMark Ultra automation staining platform. The primary antibody used was the anti-c-Met clone SP44. The OptiView DAB IHC Detection Kit was used for indirect visualization of the primary antibody for c-Met expression determination.

[0377] The procedures for staining on the Ventana Benchmark instrument included the steps of: 1) applying a slide bar code label corresponding to the SP44 IHC protocol to be performed (TABLE 3); 2) loading the SP44 antibody, Rabbit Monoclonal Negative Control Ig, and OptiView detection kit dispensers onto the reagent tray; optionally checking bulk fluids (TABLE 4) and empty waste; 3) loading slides to be examined onto the automated slide stainer; and 4) starting the staining run on the Ventana instrument.

[0378] At the completion of the Ventana instrument run, slides were removed and submerged in a mild detergent to remove the oil coverslip. Slides were rinsed thoroughly with distilled water, and then dehydrated through graded series of alcohols. Slides were cleared in xylene and a coverslip applied using a permanent mounting media. 109 158929154.28.4.2 Results and Analysis Slide Evaluation and Interpretation

[0379] Neoplastic cells stained with the c-Met SP44 OptiView IHC assay were evaluated visually for positivity based on the intensity of the diaminobenzidine (DAB) signal. The IHC signal may be distributed homogeneously throughout the neoplasm or distributed heterogeneously with few cells staining positive.

[0380] c-Met (SP44) IHC staining in NSCLC showed that membrane staining is often accompanied by cytoplasmic staining (i.e., both cytoplasmic and membranous). When the staining pattern presents as membranous, it can be either circumferential (the predominant showing), or partial (i.e., basolateral staining in adenocarcinomas). Both membranous and cytoplasmic staining showed a range of intensity varying from no staining (IHC score of 0) to strong staining (IHC score of 3+). Cytoplasmic staining was generally lower in intensity than membranous staining. Some situations showed cytoplasmic staining having a similar 110 158929154.2intensity to membrane staining (i.e., especially in cases with moderate or strong intensities), and careful differentiation between membranous from cytoplasmic staining was required.

[0381] Normal lung, bronchial epithelium, pneumocytes and alveolar macrophages generally did not show strong levels of c-Met-overexpression. However, bronchial epithelium and pneumocytes stained with an IHC score of 2+ to 3+ in a basolateral pattern. Staining in normal cellular components may be suitable for internal controls of the method. Representative staining intensity guidelines for cytoplasmic staining and membranous staining are shown in TABLE 8 and TABLE 9, respectively.111 158929154.2Scoring Algorithm

[0382] c-Met-stained tumor tissue IHC slides were evaluated for membrane staining on neoplastic cells. Non-squamous NSCLC samples with <25% 3+ membrane staining were considered c-Met negative. Non-squamous NSCLC samples with ≥25% of viable tumor cells exhibiting 3+ membrane staining were considered c-Met positive. Non-squamous NSCLC samples with ≥25% to <50% of viable tumor cells exhibiting 3+ membrane staining were considered c-Met Intermediate. Non-squamous NSCLC samples with ≥50% of viable tumor cells exhibiting 3+ membrane staining were considered c-Met High. TABLE 10 shows different intensities of membrane staining and positive / negative status per scoring algorithm.112 158929154.28.4.3 Validation Across IHC Platforms Comparison of c-Met IHC Assays: SP44 “Ultraview” to SP44 “Optiview”

[0383] An analytical method comparison between SP44 Ultraview and SP44 OptiView on a large cohort of commercial NSCLC tissues was performed (FIG.10). These results show that SP44 OptiView IHC assay selected for a similar patient population as SP44 Ultraview at the ≥25% 3+ membrane staining cutoff. The overall percent agreement at this cutoff between the two assays was 93%. A phase I clinical trial treated patients with an H-score of 150 using the SP44 UltraView assay with an anti-cMet ADC. Upon re-scoring of the slides, the optimal cutoff utilizing the SP44 Ultraview IHC assay was ≥25% 3+ with a best overall response of 56%. The best overall response for the OptiView IHC assay utilizing the phase I data through statistical modeling was 52% (FIG.11).

[0384] Similarly, the SP44 OptiView IHC assay showed a 99% overall percent agreement to the SP44 Ultraview IHC assay at the ≥50% 3+ membrane staining cutoff (FIG.12). A phase I clinical trial treated patients with an H-score of 150 using the SP44 UltraView assay with an anti-cMet ADC. Upon re-scoring of the slides, the SP44 Ultraview IHC assay showed a best overall response of 67% at the ≥50% 3+ membrane staining cutoff. The best overall response for the OptiView IHC assay utilizing the phase I data through statistical modeling was 63% (FIG.12). 8.5 Example 5: MET FISH Protocol

[0385] The SureFISH MET Amplification Probe with CEP7 FISH assay is a dual-color, spot-counting FISH assay utilizing orange probe for the MET gene in locus 7q31.2 and green probe for CEP7 to detect allelic copy numbers at the corresponding loci. Formalin-fixed, paraffin-embedded (FFPE) slides are processed, hybridized with the MET and CEP7 probes at a 1:50 dilution ratio with a buffer (tDenHyb-2™), and washed according to standard FISH protocol at NeoGenomics. Within the circled tumor region based on pathology review of serial H&E slide, 50 nucleated cells will be individually enumerated by a nationally licensed cytogenetic technologist who satisfies CAP / CLIA standard. The licensed technologist has been trained in ratio-based FISH analysis procedures with annual competency assessments and participates in bi-annual Laboratory Proficiency Testing. The scores will be evaluated based on MET / CEP7 cutoff criteria, which are listed below according to literature and will be validated by NeoGenomics. For validation reporting, enumerated FISH scores will be reviewed, and amplification status confirmed by the site medical director at NeoGenomics. 113 158929154.2For real-time clinical trial reporting, samples will have the raw data scores of the technologist interpreted for amplification status by a certified pathologist approved for the study. 8.6 Example 6: Dose Escalation Results From a First-in-Human Study of ADC1, a Novel C-Met–Targeting Antibody-Drug Conjugate, in Advanced Solid Tumors as of November 10, 2023

[0386] While c-Met expression level was originally considered as a criteria for eligibility in Parts 2 and 3 of this study, it was later discarded as a criteria for eligibility. 8.6.1 (NSCLC) Part 2 results

[0387] As of a first data cut, a total of 19 patients were enrolled in Part 2 of the study (10 patients enrolled in Part 2i, 5 patients enrolled in Part 2ii, and 4 patients enrolled in Part 2iii).

[0388] FIG.13A shows percentage change in target lesion measurement from baseline over time in patients with EGFR-wt non-squamous (NSQ) NSCLC (part 2i),EGFR-mu non- squamous NSCLC (part 2ii) and squamous NSCLC (part 2iii) (N=16).

[0389] The best ORR, confirmed ORR, and confirmed CBR in patients with EGFR-wt non- squamous NSCLC were 40%, 30%, and 70%, respectively. The best ORR, confirmed ORR, and confirmed CBR in patients with EGFR-mu non-squamous NSCLC were 80%, 80%, and 80%, respectively. The best ORR, confirmed ORR, and confirmed CBR in patients with squamous NSCLC were 0%, 0%, and 25%, respectively.

[0390] As of a second data cut, 48 subjects with 2L+ NSQ NSCLC-EGFR-wt were enrolled in Part 2i; 11 subjects with c-Met expression ≥25% 3+, 10 subjects with c-Met expression ranging between ≥ 50% 2+ and < 25% 3+, and 27 subjects c-Met unselected.

[0391] The Part 2i second data cut confirmed objective response rate (ORR) by investigator assessment was 43.8% (21 / 48) and the unconfirmed best overall response rate was 54.2% (26 / 48). The confirmed clinical benefit rate at 12 weeks (CBR12) was 62.5% (30 / 48). The confirmed clinical benefit rate at 24 weeks (CBR24) was 47.9% (23 / 48). With the majority of patients on treatment (62.5%) as of the second data cut, duration of response (DOR) was 5.5 months across the 21 responders, and the median progression-free survival (PFS) and overall survival (OS) were 6.9 and 12.0 months, respectively. FIG.13B shows percentage change in target lesion measurement from baseline over time in patients with EGFR-wt non-squamous NSCLC (part 2i) as of the second data cut.

[0392] Subjects with NSQ NSCLC tumors that had a positive c-Met expression level for NSCLC (defined by ≥50% of neoplastic cells from tumor tissue assessed by c-Met IHC 114 158929154.2having at least 2+ membrane or membrane + cytoplasm staining (≥50% 2+)) exhibited an ORR of 48.6%. Subjects with tumors not meeting the ≥50% 2+ threshold experienced an ORR of 30%. Subjects with NSQ NSCLC tumors that had a positive c-Met expression level for NSCLC (defined by ≥25% of neoplastic cells from tumor tissue assessed by c-Met IHC having 3+ membrane or membrane + cytoplasm staining (≥25% 3+)) exhibited an ORR of 53.3%. Subjects with tumors not meeting the ≥25% 3+ threshold experienced an ORR of 40.6%. The below Table summarizes the ORR observed in EGFR-wt NSQ NSCLC tumors by IHC cutoff.

[0393] Table 11. ORR observed in EGFR-wt NSQ NSCLC tumors by IHC cutoff

[0394] For subjects enrolled in part 2ii with EGFR-mu NSQ NSCLC tumors the ORR was 37.9%. For subjects with EGFR-mu NSQ NSCLC tumors with c-Met expression of ≥25% 3+, the ORR was 46.2%. The below Table summarizes the ORR observed in EGFR-mu NSQ NSCLC tumors by IHC cutoff.

[0395] Table 12. ORR observed in EGFR-mu NSQ NSCLC tumors by IHC cutoff115 158929154.28.6.2 (GEA) Part 3 results

[0396] As of a first data cut, a total of 22 patients were enrolled in Part 3 of the study. FIG. 14A shows percentage change in target lesion measurement from baseline over time in patients with GEA (N=22). The best ORR, confirmed ORR, and confirmed CBR in patients with GEA with one prior therapy were 40%, 30%, and 80%, respectively. The best ORR, confirmed ORR, and confirmed CBR in patients in patients with GEA with two or more prior therapies were 36%, 27%, and 63%, respectively.

[0397] As of a second data cut, 42 subjects with 2L+ GEA were enrolled. Initially, patients were prospectively selected for enrollment based upon c-Met expression >90% 1+ cut-off; however, due to greater than 80% of prescreening patients meeting the prespecified selection criteria, the prospective selection requirement was removed. Of the 42 GEA patients enrolled, 20 were enrolled using the prospective c-Met selection (>90% 1+ cut-off) and 22 were enrolled in an unselected manner.

[0398] In Part 3 patients with GEA, the investigator assessed confirmed objective response rate (ORR) was 28.6% (12 / 42). One complete response was observed. The confirmed clinical benefit rate (CBR) was 71.4%. The confirmed clinical benefit rate at 12 weeks (CBR12) was 40.5% (17 / 42). DOR was 4.2 months across the 12 responders. The median progression-free survival (PFS) and overall survival (OS) were 3.98 and 5.95 months, respectively.

[0399] FIG.14B shows percentage change in target lesion measurement from baseline over time in patients with GEA from the second data cut (N=41).

[0400] The best ORR, confirmed ORR, and confirmed CBR in patients with GEA with one prior therapy were 40%, 30%, and 80%, respectively. The best ORR, confirmed ORR, and confirmed CBR in patients in patients with GEA with two or more prior therapies were 36%, 27%, and 63%, respectively.

[0401] Subjects with GEA tumors that had a positive c-Met expression level for GEA (defined by ≥50% of neoplastic cells from tumor tissue assessed by c-Met IHC having 2+ membrane or membrane + cytoplasm staining (≥50% 2+)) exhibited an ORR of 37.9%. Subjects with tumors not meeting the ≥50% 2+ threshold experienced an ORR of 7.7%.

[0402] Table 13. ORR observed in GEA tumors by IHC cutoff. 116 158929154.2

[0403] Subjects with GEA tumors that were positive for MET gene amplification had on ORR of 58%, versus 17% for those subjects who had tumors not positive for MET gene amplification. When amplifications due to aneuploidy were excluded, the ORR was 78%, versus 16% for those having tumors that were not positive for focal MET gene amplification.

[0404] Table 14. ORR observed in GEA tumors by MET Amplification.8.6.3 (CRC) Part 1 (monotherapy dose escalation) and part 4 (colorectal cancer) results

[0405] As of a first data cut, 29 patients were enrolled in Part 1 and 93 patients were enrolled in Part 4 of the study, for a total of 122.

[0406] FIGS.15A – 15B show percentage change in target lesion measurement from baseline over time in patients with CRC in Part 1 (FIG.15A; N=26) and patients with CRC in Part 4 (FIG.15B; N= 86)).

[0407] The ORR, and CBR in patients who received 1.6 mg / kg of ADC1 in Parts 1 and 4 combined are 6% and 75%, respectively. The ORR and CBR in patients who received 2.4 mg / kg of ADC1 in Parts 1 and 4 combined are 18% and 78%, respectively. The ORR and CBR in patients who received 3.0 mg / kg of ADC1 in Parts 1 and 4 combined are 24% and 117 158929154.268%, respectively. Median progression free survival was 5.1 months for patients receiving 1.6 mg / kg, 5.3 months for patients receiving 2.4 mg / kg, and 4.1 months for those receiving 3.0 mg / kg. Median overall survival was 9.63 months for patients receiving 2.4 mg / kg, and 9.2 months for those receiving 3.0 mg / kg. Median duration of response was 5.32 months for patients receiving 2.4 mg / kg, and 4.14 months for those receiving 3.0 mg / kg.

[0408] Higher ADC exposure correlated with higher probability of response (e.g., ORR and CBR). Doses of both 2.4 and 3.0 mg / kg of ADC1 composition exhibited efficacy with 2.4 mg / kg exhibited a better safety profile and overall tolerability. 8.6.4 (MET amplification) Part 5 Results

[0409] As of a first data cut, 29 patients were enrolled in Part 5 of the study.

[0410] FIG.16 shows percentage change in target lesion measurement from baseline over time in patients with MET Amplified tumors (N=27).

[0411] The best ORR, confirmed ORR, and confirmed CBR in patients who received 2.4 mg / kg of ADC1 are 36.4%, 36.4%, and 81.8%, respectively. The best ORR, confirmed ORR, and confirmed CBR in patients who received 3.0 mg / kg of ADC1 are 75.1%, 62.5%, and 87.5%, respectively. 8.6.5 Summary of Treatment Emergent Adverse Events All Treatment Groups

[0412] Table 15: Summary of Treatment Adverse Events (TAEs) across all indications and for GEA only as of a first data cut.118 158929154.2Table 16: Summary of Treatment Adverse Events (TAEs) across all indications and for GEA only as of a second data cut. 119 158929154.2

[0413] Hematological toxicities are the most dose-limiting toxicities but were well managed at doses ≤3 mg / kg.

[0414] All references cited herein are incorporated herein by reference in their entireties and for all purposes to the same extent as if each individual publication or patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety for all purposes. 120 158929154.2

Claims

CLAIMS WHAT IS CLAIMED:

1. A method of treating a non-squamous non-small cell lung cancer (“NSCLC”) tumor that expresses c-Met, comprising administering intravenously every three weeks to a human subject or population of human subjects having said NSCLC tumor a therapeutically effective amount of 1.6 mg / kg, 2.4 mg / kg, 3.0 mg / kg, 3.5 mg / kg, 4.0 mg / kg, or 6.0 mg / kg of an anti-c-Met antibody drug conjugate (“anti-c-Met ADC”) having the following structure:wherein n is 2, 4, 6, 8, or 10, and wherein Ab is telisotuzumab, thereby treating said NSCLC tumor.

2. The method of claim 1, wherein the NSCLC is refractory or relapsed.

3. The method of embodiment 1 or 2, further comprising the step of determining the c- Met expression level of the tumor.

4. The method of any one of claims 1-3, wherein the NSCLC tumor expresses wild type epidermal growth factor receptor (EGFR-wt).

5. The method of any one of claims 1-3, wherein the NSCLC tumor expresses mutated EGFR (EGFR-mu).

6. The method of any one of claims 1-3, wherein the NSCLC tumor is non-squamous NSCLC tumor with EGFR-wt expression.

7. The method of any one of claims 1-3, wherein the NSCLC tumor is non-squamous NSCLC tumor with EGFR-mu expression. 121 158929154.

28. The method of any one of claims 1-3, wherein the tumor harbors a MET gene mutation.

9. The method of any one of claims 1-3, wherein the NSCLC tumor is an advanced solid tumor that has progressed on all standard of care therapy and is not amenable to surgical resection or other approved therapeutic options that have demonstrated clinical benefit.

10. The method of claim 6 or 8, wherein the NSCLC tumor has progressed after treatment with at least platinum-based chemotherapy and an immune checkpoint inhibitor and / or appropriate targeted therapy.

11. The method of claim 7, wherein the NSCLC tumor has progressed after treatment with at least platinum-based chemotherapy doublet and / or tyrosine kinase inhibitor(s).

12. The method of any one of claims 6-8 and 10-11, wherein the human subject has had no more than 2 lines of prior cytotoxic chemotherapy excluding adjuvant therapy.

13. The method of any one of claims 1-12, wherein administration of the anti-c-Met ADC provides an overall response rate that is greater than 25%, greater than 30%, greater than 35%, greater than 40%, greater than 45%, greater than 50%, greater than 55%, greater than 60%, greater than 65%, greater than 70%, greater than 75%, or greater than 80%.

14. The method of any one of claims 1-13, wherein administration of the anti-c-Met ADC achieves a partial response (PR) in the human subject.

15. The method of any one of claims 1-13, wherein administration of the anti-c-Met ADC achieves a complete response (CR) in the human subject.

16. The method of any one of claims 1-13, wherein administration of the anti-c-Met ADC achieves stable disease (SD) in the human subject.

17. The method of any one of claims 1-16, wherein n has a value of 2.

18. The method of any one of claims 1-16, wherein n has a value of 4.

19. The method of any one of claims 1-16, wherein n has a value of 6.

20. The method of any one of claims 1-16, wherein n has a value of 8. 122 158929154.

221. The method of any one of claims 1-16, wherein n has a value of 10.

22. The method of any one of claims 1-21, wherein the anti-c-Met ADC has an average drug-antibody ratio (DAR) of about 5.4 to about 6.

6.

23. The method of any one of claims 1-21, wherein the NSCLC tumor is a refractory or relapsed NSCLC tumor, wherein a therapeutically effective amount of 2.4 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to the human subject, wherein the anti-c-Met ADC has an average DAR of about 6, and wherein administration of the anti-c-Met ADC achieves PR in the human subject.

24. The method of any one of claims 1-21, wherein the NSCLC tumor is a refractory or relapsed NSCLC tumor, wherein a therapeutically effective amount of 3.0 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to the human subject, wherein the anti-c-Met ADC has an average DAR of about 6, and wherein administration of the anti-c-Met ADC achieves PR in the human subject.

25. The method of any one of claims 1-21 and 23, wherein the NSCLC tumor is a refractory or relapsed NSCLC tumor, wherein a therapeutically effective amount of 2.4 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to a plurality of human subjects, wherein the anti-c-Met ADC has an average DAR of about 6, and wherein administration of the anti-c-Met ADC provides an overall response rate that is greater than 25%.

26. The method of any one of claims 1-21 and 24, wherein the NSCLC tumor is a refractory or relapsed NSCLC tumor, wherein a therapeutically effective amount of 3.0 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to a plurality of human subjects, wherein the anti-c-Met ADC has an average DAR of about 6, and wherein administration of the anti-c-Met ADC provides an overall response rate that is greater than 25%.

27. A method of treating a gastroesophageal adenocarcinoma (“GEA”) tumor that expresses c-Met, comprising administering intravenously every three weeks to a human subject or population of human subjects having said GEA tumor a therapeutically effective amount of 1.6 mg / kg, 2.4 mg / kg, 3.0 mg / kg, 3.5 mg / kg, 4.0 mg / kg, or 6.0 mg / kg of an anti-c-Met ADC having the following structure: 123 158929154.2wherein n is 2, 4, 6, 8, or 10, and wherein Ab is telisotuzumab, thereby treating said GEA tumor.

28. The method of claim 27, wherein the GEA tumor is refractory or relapsed.

29. The method of claim 27 or 28, further comprising the step of determining the c-Met expression level of the tumor.

30. The method of claim 27 or 28, wherein the GEA tumor harbors a MET gene mutation.

31. The method of any one of claims 27-30, wherein the GEA tumor is advanced histopathologically or cytologically confirmed c-Met expressing GEA that has progressed after treatment with at least 1 prior cytotoxic chemotherapeutic regimen for locally advanced or metastatic disease and is not amenable to surgical resection, and the human subject has not received more than 2 prior lines of cytotoxic chemotherapy regimens.

32. The method of claim 30 or 31, wherein the GEA tumor has progressed on an immune checkpoint inhibitor.

33. The method of any one of claims 30-32, wherein the GEA tumor has progressed on HER2-directed therapies.

34. The method of any one of claims 27-33, wherein administration of the anti-c-Met ADC provides an overall response rate that is greater than 25%, greater than 30%, greater than 35%, greater than 40%, greater than 45%, greater than 50%, greater than 55%, greater than 60%, greater than 65%, greater than 70%, greater than 75%, or greater than 80%. 124 158929154.

235. The method of any one of claims 27-34, wherein administration of the anti-c-Met ADC achieves a partial response (PR) in the human subject.

36. The method of any one of claims 27-34, wherein administration of the anti-c-Met ADC achieves a complete response (CR) in the human subject.

37. The method of any one of claims 27-34, wherein administration of the anti-c-Met ADC achieves stable disease (SD) in the subject.

38. The method of any one of claims 27-37, wherein n has a value of 2.

39. The method of any one of claims 27-37, wherein n has a value of 4.

40. The method of any one of claims 27-37, wherein n has a value of 6.

41. The method of any one of claims 27-37, wherein n has a value of 8.

42. The method of any one of claims 27-37, wherein n has a value of 10.

43. The method of any one of claims 27-42, wherein the anti-c-Met ADC has an average DAR of about 5.4 to about 6.

6.

44. The method of any one of claims 27-42, wherein the GEA tumor is a refractory or relapsed GEA tumor, wherein a therapeutically effective amount of 2.4 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to the human subject, wherein the anti-c-Met ADC has an average DAR of about 6, and wherein administration of the anti-c-Met ADC achieves PR in the human patient.

45. The method of any one of claims 27-42, wherein the GEA tumor is a refractory or relapsed GEA tumor, wherein a therapeutically effective amount of 3.0 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to the human subject, wherein the anti-c-Met ADC has an average DAR of about 6, and wherein administration of the anti-c-Met ADC achieves PR in the human patient.

46. The method of any one of claims 27-42 and 44, wherein the GEA tumor is a refractory or relapsed GEA tumor, wherein a therapeutically effective amount of 2.4 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to a plurality of human subjects, wherein the anti-c-Met ADC has an average DAR of about 6, and wherein administration of the anti-c-Met ADC provides an overall response rate that is greater than 25%. 125 158929154.

247. The method of any one of claims 27-42 and 45, wherein the GEA tumor is a refractory or relapsed GEA tumor, wherein a therapeutically effective amount of 3.0 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to a plurality of human subjects, wherein the anti-c-Met ADC has an average DAR of about 6, and wherein administration of the anti-c-Met ADC provides an overall response rate that is greater than 25%.

48. A method of treating a colorectal cancer (“CRC”) tumor that expresses cMet, comprising administering intravenously every three weeks to a human subject or population of human subjects having said CRC tumor a therapeutically effective amount of 1.6 mg / kg, 2.4 mg / kg, 3.0 mg / kg, 3.5 mg / kg, 4.0 mg / kg, or 6.0 mg / kg of an anti-c-Met ADC having the following structure:wherein n is 2, 4, 6, 8, or 10, and wherein Ab is telisotuzumab, thereby treating said CRC tumor.

49. The method of claim 48, wherein the CRC tumor is refractory or relapsed.

50. The method of claim 48 or 49, further comprising the step of determining the c-Met expression level of the tumor.

51. The method of any one of claims 48-50, wherein the CRC tumor is advanced histopathologically or cytologically confirmed CRC that does not harbor the BRAF V600E mutation and is not dMMR+ / MSI-Hi.

52. The method of claim 51, wherein the CRC tumor has progressed on any one or a combination of prior treatments including a fluoropyrimidine, oxaliplatin, irinotecan, 126 158929154.2an anti-EGFR antibody, and / or an anti-vascular endothelial growth factor monoclonal antibody.

53. The method of claim 51 or 52, wherein the CRC tumor has progressed on an applicable targeted therapy.

54. The method of any one of claims 48-53, wherein administration of the anti-c-Met ADC provides an overall response rate that is greater than 25%, greater than 30%, greater than 35%, greater than 40%, greater than 45%, greater than 50%, greater than 55%, greater than 60%, greater than 65%, greater than 70%, greater than 75%, or greater than 80%.

55. The method of any one of claims 48-53, wherein administration of the anti-c-Met ADC achieves a partial response (PR) in the human subject.

56. The method of any one of claims 48-53, wherein administration of the anti-c-Met ADC achieves a complete response (CR) in the human subject.

57. The method of any one of claims 48-53, wherein administration of the anti-c-Met ADC achieves stable disease (SD) in the human subject.

58. The method of any one of claims 48-57, wherein n has a value of 2.

59. The method of any one of claims 48-57, wherein n has a value of 4.

60. The method of any one of claims 48-57, wherein n has a value of 6.

61. The method of any one of claims 48-57, wherein n has a value of 8.

62. The method of any one of claims 48-57, wherein n has a value of 10.

63. The method of any one of claims 48-62, wherein the anti-c-Met ADC has an average DAR of about 5.4 to about 6.

6.

64. The method of any one of claims 48-62, wherein the CRC tumor is a refractory or relapsed CRC tumor, wherein a therapeutically effective amount of 2.4 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to the human subject, wherein the anti-c-Met ADC has an average DAR of about 6, and wherein administration of the anti-c-Met ADC achieves PR in the human subject. 127 158929154.

265. The method of any one of claims 48-62, wherein the CRC tumor is a refractory or relapsed CRC tumor, wherein a therapeutically effective amount of 3.0 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to the human subject, wherein the anti-c-Met ADC has an average DAR of about 6, and wherein administration of the anti-c-Met ADC achieves PR in the human subject.

66. The method of any one of claims 48-62 and 64, wherein the CRC tumor is a refractory or relapsed CRC tumor, wherein a therapeutically effective amount of 2.4 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to a plurality of human subjects, wherein the anti-c-Met ADC has an average DAR of about 6, and wherein administration of the anti-c-Met ADC provides an overall response rate that is greater than 25%.

67. The method of any one of claims 48-62 and 65, wherein the CRC tumor is a refractory or relapsed CRC tumor, wherein a therapeutically effective amount of 3.0 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to a plurality of human subjects, wherein the anti-c-Met ADC has an average DAR of about 6, and wherein administration of the anti-c-Met ADC provides an overall response rate that is greater than 25%.

68. The method of claim 48, wherein the tumor harbors a MET gene mutation.

69. A method of treating a MET gene amplified advanced solid tumor that expresses cMet, comprising administering intravenously every three weeks to a human subject or population of human subjects having said MET gene amplified advanced tumor a therapeutically effective amount of 1.6 mg / kg, 2.4 mg / kg, 3.0 mg / kg, 3.5 mg / kg, 4.0 mg / kg, or 6.0 mg / kg of an anti-c-Met ADC having the following structure:128 158929154.2wherein n is 2, 4, 6, 8, or 10, and wherein Ab is telisotuzumab, thereby treating said MET gene amplified advanced solid tumor.

70. The method of claim 69, wherein the MET gene amplified advanced solid tumor is refractory or relapsed.

71. The method of claim 69 or 70, wherein n has a value of 2.

72. The method of claim 69 or 70, wherein n has a value of 4.

73. The method of claim 69 or 70, wherein n has a value of 6.

74. The method of claim 69 or 70, wherein n has a value of 8.

75. The method of claim 69 or 70, wherein n has a value of 10.

76. The method of any one of claims 69-75, wherein the anti-c-Met ADC has an average DAR of about 5.4 to about 6.

6.

77. The method of any one of claims 69-75, wherein the MET gene amplified advanced solid tumor is a refractory or relapsed MET gene amplified advanced solid tumor, wherein a therapeutically effective amount of 2.4 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to the human subject, wherein the anti- c-Met ADC has an average DAR of about 6, and wherein administration of the anti-c- Met ADC achieves PR in the human subject.

78. The method of any one of claims 69-75, wherein the MET gene amplified advanced solid tumor is a refractory or relapsed MET gene amplified advanced solid tumor, wherein a therapeutically effective amount of 3.0 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to the human subject, wherein the anti- c-Met ADC has an average DAR of about 6, and wherein administration of the anti-c- Met ADC achieves PR in the human subject.

79. The method of any one of claims 69-75 and 77, wherein the MET gene amplified advanced solid tumor is a refractory or relapsed MET gene amplified advanced solid tumor, wherein a therapeutically effective amount of 2.4 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to a plurality of human subjects, wherein the anti-c-Met ADC has an average DAR of about 6, and wherein 129 158929154.2administration of the anti-c-Met ADC provides an overall response rate that is greater than 25%.

80. The method of any one of claims 69-75 and 78, wherein the MET gene amplified advanced solid tumor is a refractory or relapsed MET gene amplified advanced solid tumor, wherein a therapeutically effective amount of 3.0 mg / kg of the anti-c-Met ADC is administered intravenously every three weeks to a plurality of human subjects, wherein the anti-c-Met ADC has an average DAR of about 6, and wherein administration of the anti-c-Met ADC provides an overall response rate that is greater than 25%.

81. The method of claim 69, wherein the tumor harbors a MET gene mutation.

82. A method of treating a colorectal cancer (“CRC”) tumor that expresses c-Met, comprising administering intravenously every four weeks to a human subject or population of human subjects having said CRC tumor a therapeutically effective amount of 1.6 mg / kg, 2.4 mg / kg, or 3.0 mg / kg of an anti-c-Met ADC having the following structure:wherein n is 2, 4, 6, 8, or 10, and wherein Ab is telisotuzumab, and wherein the method further comprises: a) administering intravenously every two weeks 200 mg / 2of folinic acid; b) administering intravenously every two weeks 2400 mg / m2of 5-FU; and c) administering intravenously every two weeks 5 mg / kg of bevacizumab to the subject, thereby treating said CRC tumor.

83. The method of claim 82, wherein the CRC tumor is relapsed or refractory.

84. The method of claim 82, wherein the CRC tumor is unresectable. 130 158929154.

285. The method of claim 82, further comprising the step of determining the c-Met expression level of the tumor.

86. The method of claim 82, wherein the tumor harbors a MET gene mutation.

87. A method of treating a colorectal cancer (“CRC”) tumor that expresses c-Met, comprising administering intravenously every two weeks to a human subject having said CRC tumor a therapeutically effective amount of 0.8 mg / kg, 1.0 mg / kg, 1.2 mg / kg, 1.6 mg / kg, 2.0 mg / kg, or 2.4 mg / kg of an anti-c-Met ADC having the following structure:wherein n is 2, 4, 6, 8, or 10, and wherein Ab is telisotuzumab, and wherein the method further comprises: a) administering intravenously every two weeks 200 mg / 2of folinic acid; b) administering intravenously every two weeks 2400 mg / m2of 5-FU; and c) administering intravenously every two weeks 5 mg / kg of bevacizumab to the subject, thereby treating said CRC tumor.

88. The method of claim 87, wherein the CRC tumor is relapsed or refractory.

89. The method of claim 87, wherein the CRC tumor is unresectable.

90. The method of claim 87, further comprising the step of determining the c-Met expression level of the tumor.

91. The method of claim 87, wherein the tumor harbors a MET gene mutation.

92. A method of treating a hepatocellular carcinoma (“HCC”) tumor that expresses c-Met, comprising administering intravenously every three weeks to a human subject or population of human subjects having said HCC tumor a therapeutically effective amount of 1.6 mg / kg, 2.0 mg / kg, 2.4 mg / kg, or 3.0 mg / kg of an anti-c-Met ADC having the following structure: 131 158929154.2wherein n is 2, 4, 6, 8, or 10, and wherein Ab is telisotuzumab, thereby treating said HCC tumor.

93. The method of claim 93, wherein the HCC tumor is relapsed or refractory.

94. The method of claim 93, wherein the HCC tumor is unresectable.

95. The method of claim 93, further comprising the step of determining the c-Met expression level of the tumor.

96. A method of treating a biliary tract cancer (“BTC”) tumor that expresses c-Met, comprising administering intravenously every three weeks to a human subject or population of human subjects having said BTC tumor a therapeutically effective amount of 1.6 mg / kg, 2.0 mg / kg, 2.4 mg / kg, or 3.0 mg / kg of an anti-c-Met ADC having the following structure:wherein n is 2, 4, 6, 8, or 10, and wherein Ab is telisotuzumab, thereby treating said BTC tumor.

97. The method of claim 97, wherein the BTC tumor is relapsed or refractory.

98. The method of claim 97, wherein the BTC tumor is unresectable.

99. The method of claim 97, further comprising determining the c-Met expression level of the tumor.

100. The method of claim 93, wherein the tumor harbors a MET gene mutation. 132 158929154.2101. A method of treating a pancreatic ductal adenocarcinoma (“PDAC”) tumor that expresses c-Met, comprising administering intravenously every three weeks to a human subject or population of human subjects having said PDAC tumor a therapeutically effective amount of 1.6 mg / kg, 2.0 mg / kg, 2.4 mg / kg, or 3.0 mg / kg of an anti-c-Met ADC having the following structure:wherein n is 2, 4, 6, 8, or 10, and wherein Ab is telisotuzumab, thereby treating said PDAC tumor.

102. The method of claim 102, wherein the PDAC tumor is relapsed or refractory.

103. The method of claim 102, wherein the PDAC tumor is unresectable.

104. The method of claim 102, further comprising the step of determining the c-Met expression level of the tumor.

105. The method of claim 102, wherein the tumor harbors a MET gene mutation.

106. A method of treating an esophageal squamous cell carcinoma (“ESCC”) tumor that expresses c-Met, comprising administering intravenously every three weeks to a human subject having said ESCC tumor a therapeutically effective amount of 1.6 mg / kg, 2.0 mg / kg, 2.4 mg / kg, or 3.0 mg / kg of an anti-c-Met ADC having the following structure:133 158929154.2wherein n is 2, 4, 6, 8, or 10, and wherein Ab is telisotuzumab, thereby treating said ESCC tumor.

107. The method of claim 107, wherein the ESCC tumor is relapsed or refractory.

108. The method of claim 107, wherein the ESCC tumor is unresectable.

109. The method of claim 107, further comprising the step of determining the c-Met expression level of the tumor.

110. The method of claim 107, wherein the tumor harbors a MET gene mutation.

111. A method of treating a triple-negative breast cancer tumor (“TNBC”) tumor that expresses c-Met, comprising administering intravenously every three weeks to a human subject or population of human subjects having said TNBC tumor a therapeutically effective amount of 1.6 mg / kg, 2.0 mg / kg, 2.4 mg / kg, or 3.0 mg / kg of an anti-c-Met ADC having the following structure:wherein n is 2, 4, 6, 8, or 10, and wherein Ab is telisotuzumab, thereby treating said TNBC tumor.

112. The method of claim 112, wherein the TNBC tumor is relapsed or refractory.

113. The method of claim 112, wherein the TNBC tumor is unresectable.

114. The method of claim 112, further comprising the step of determining the c-Met expression level of the tumor.

115. The method of claim 112, wherein the tumor harbors a MET gene mutation.

116. A method of treating a hormone receptor-positive / human epidermal growth factor receptor 2-negative breast cancer tumor (“HR+ / HER2- BC”) tumor that expresses c- Met, comprising administering intravenously every three weeks to a human subject or population of human subjects having said HR+ / HER2- BC tumor a therapeutically effective amount of 1.6 mg / kg, 2.0 mg / kg, 2.4 mg / kg, or 3.0 mg / kg of an anti-c-Met ADC having the following structure: 134 158929154.2wherein n is 2, 4, 6, 8, or 10, and wherein Ab is telisotuzumab, thereby treating said HR+ / HER2- BC tumor.

117. The method of claim 117, wherein the HR+ / HER2- BC tumor is relapsed or refractory.

118. The method of claim 117, further comprising the step of determining the c-Met expression level of the tumor.

119. The method of claim 117, wherein the HR+ / HER2- BC tumor is unresectable.

120. The method of claim 117, wherein the tumor harbors a MET gene mutation.

121. A method of treating a head and neck squamous cell carcinoma (“HNSCC”) tumor that expresses c-Met, comprising administering intravenously every three weeks to a human subject or population of human subjects having said HNSCC tumor a therapeutically effective amount of 1.6 mg / kg, 2.0 mg / kg, 2.4 mg / kg, or 3.0 mg / kg of an anti-c-Met ADC having the following structure:wherein n is 2, 4, 6, 8, or 10, and wherein Ab is telisotuzumab, thereby treating said HNSCC tumor.

122. The method of claim 122, wherein the HNSCC tumor is relapsed or refractory. 135 158929154.2123. The method of claim 122, further comprising the step of determining the c-Met expression level of the tumor.

124. The method of claim 122, wherein the HNSCC tumor is unresectable.

125. The method of claim 122, wherein the tumor harbors a MET gene mutation. 136 158929154.2

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